DK169922B1 - Substituted (imidazol-4-yl) methylpyrido, and -azepino, indolone derivatives, process for their preparation, and pharmaceutical compositions containing the derivatives - Google Patents

Abstract

The invention relates to tricyclic lactams of the general formula (I) <CHEM> wherein Im represents an imidazolyl group of the formula: <CHEM> and R<1> represents a hydrogen atom or a group selected from C1-6alkyl, C3-6alkenyl, C3-10alkynyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl-, phenyl, phenylC1-3alkyl-, -CO2R<5>, -COR<5>, -CONR<5>R<6> or -SO2R<5> (wherein R<5> and R<6>, which may be the same or different, each represents a hydrogen atom, a C1-6alkyl or C3-7cycloalkyl group, or a phenyl or phenylC1-4alkyl- group, in which the phenyl group is optionally substituted by one or more C1-4alkyl, C1-4alkoxy or hydroxy groups or halogen atoms, with the proviso that R<5> does not represent a hydrogen atom when R<1> represents a group -CO2R<5> or -SO2R<5>); one of the groups represented by R<2>, R<3> and R<4> is a hydrogen atom or a C1-6alkyl, C3-7cycloalkyl, C3-6alkenyl, phenyl or phenylC1-3alkyl- group, and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C1-6alkyl group; Y represents the group CH=CH or (CH2)n, wherein n represents 2 or 3; Q represents a halogen atom, or a group selected from hydroxy, C1-4alkoxy, phenylC1-3alkoxy-, C1-6alkyl, cyano, phenyl which may be unsubstituted or substituted by one or more C1-4alkyl, C1-4alkoxy or hydroxy groups or halogen atoms, -NR<7>R<8>, -CONR<7>R<8> or -(CH2)pCONR<7>R<8> (wherein R<7> and R<8>, which may be the same of different, each represents a hydrogen atom or a C1-4alkyl or C3-4alkenyl group, or together with the nitrogen atom to which they are attached form a saturated 5 to 7 membered ring; and p represents 1,2 or 3), -(CH2)qNR<9>R<1><0> (wherein R<9> represents a hydrogen atom or a C1-4alkyl group, and R<1><0> represents a group -COR<1><1> or -SO2R<1><1> wherein R<1><1> represents a C1-4alkyl group; and q represents 0, 1, 2 or 3), or -(CH2)2CO2R<1><1>(R<1><1> being as defined previously); Q min represents a hydrogen or a fluorine atom; and physiologically acceptable salts and solvates thereof. The compounds are potent and selective antagonists of the effect of 5-HT at 5-HT3 receptors and are useful, for example, in the treatment of psychotic disorders, anxiety, and nausea and vomiting.

Description

DK 169922 B1DK 169922 B1

Den foreliggende opfindelse angår hidtil ukendte substituerede (imidazol-4-yl)methylpyrido-, og -azepino-, indolonderiva-ter, fremgangsmåder til fremstilling deraf og farmaceutiske præparater indeholdende dem.The present invention relates to novel substituted (imidazol-4-yl) methylpyrido and azepino, indolone derivatives, processes for their preparation and pharmaceutical compositions containing them.

5 Opfindelsen angår forbindelser, som er potente og selektive antagonister for 5-hydroxytryptamin (5-HT) ved 5-HT receptorer af den type, der befinder sig på primære, afferente nerveender. Receptorer af denne type betegnes nu 5-HT3-receptorer og er også til stede i det centrale nervesystem. 5-HT 10 forekommer udbredt i de neuronale baner i det centrale nervesystem, og det er kendt, at forstyrrelse af disse baner indeholdende 5-HT ændrer adfærdssyndromer såsom sindsstemning, psykomotorisk aktivitet, appetit og hukommelse.The invention relates to compounds which are potent and selective antagonists of 5-hydroxytryptamine (5-HT) at 5-HT receptors of the type present on primary afferent nerve endings. Receptors of this type are now referred to as 5-HT3 receptors and are also present in the central nervous system. 5-HT 10 is prevalent in the neuronal pathways of the central nervous system, and disruption of these pathways containing 5-HT is known to alter behavioral syndromes such as mood, psychomotor activity, appetite, and memory.

Forbindelser med antagonistaktivitet ved 5-HT3-receptorer er 15 tidligere beskrevet.Compounds with antagonist activity at 5-HT 3 receptors have been previously described.

Således beskriver fx DE 3740352 forbindelser, som kan angives ved den almene formel: 0Thus, for example, DE 3740352 discloses compounds which may be represented by the general formula: 0

IIII

• · B• · B

// \ / W V// \ / W V

• ·-· A Im• · - · A Im

5-+ 11 11 Ju N5- + 11 11 Yes N

\ Λ /* n\ Λ / * n

• N• N

hvor Im betegner en imidazolylgruppe med formlen: /' /' > .......» · —·where Im represents an imidazolyl group of the formula: / '/'> ....... »· - ·

fi rift3 eller R3N Nfi rift3 or R3N N

\\ / \ // ]> h 20 R1 betegner hydrogen eller en gruppe valgt blandt C1.6-alkyl, C3. g - alkenyl, C3.1Q-alkynyl, C3_7-cycloalkyl, C3.7-cycloalkyl- 2 DK 169922 B1represents hydrogen or a group selected from C1-6 alkyl, C3. g - alkenyl, C3.1-alkynyl, C3-7-cycloalkyl, C3-7-cycloalkyl-2 DK-169922 B1

Ci.4-alkyl, phenyl, phenyl-C^-alkyl -, -C02R5, -COR5, -CONR5R6 eller -S02R5 (hvor R5 og R6, som kan være ens eller forskellige, hver betegner hydrogen, C-^g-alkyl eller C3.7-cycloalkyl, eller phenyl eller phenyl-C·,^-alkyl, hvor phe-5 nylgruppen eventuelt er substitueret med én eller flere C1.4-alkyl-, C1.4-alkoxy- eller hydroxygrupper eller halogenatomer, med det forbehold at R5 ikke betegner hydrogen, når R1 betegner -C02R5 eller -S02R5) ; én af grupperne R2, R3 og R4 betegner hydrogen eller C-^g-10 alkyl, C3.7-cycloalkyl, C3.g-alkenyl, phenyl eller phenylC·^-alkyl, og hver af de to andre grupper, som kan være ens eller forskellige, betegner hydrogen eller Cx_6-alkyl; Q betegner hydrogen eller halogen, hydroxy, C1.4-alkoxy, phenyl-C1.3-alkoxy eller C1.6-alkyl eller -NR7R8 eller 15 -C0NR7R8 (hvor R7 og R8, som kan være ens eller forskellige, hver betegner hydrogen eller C1.4-alkyl eller C3.4-alkenyl eller sammen med det nitrogenatom, hvortil de er bundet, danner en mættet 5- til 7-leddet ring); n betegner tallet 1, 2 eller 3; 20 og A-B betegner gruppen CH-CH2 eller C=CH; og fysiologisk acceptable salte og solvater deraf.C 1-4 alkyl, phenyl, phenyl-C 1-6 alkyl, -CO 2 R 5, -COR 5, -CONR 5 R 6 or -SO 2 R 5 (wherein R 5 and R 6, which may be the same or different, each represent hydrogen, C 1-6 alkyl or C 3-7 cycloalkyl, or phenyl or phenyl C 1-6 alkyl, wherein the phenyl group is optionally substituted by one or more C 1-4 alkyl, C 1-4 alkoxy or hydroxy groups or halogen atoms, with provided that R 5 does not represent hydrogen when R 1 represents -CO 2 R 5 or -SO 2 R 5); one of the groups R 2, R 3 and R 4 represents hydrogen or C 1-6 alkyl, C 3-7 cycloalkyl, C 3-8 alkenyl, phenyl or phenylC 1-4 alkyl, and each of the other two groups which may be the same or different, represents hydrogen or C 1-6 alkyl; Q represents hydrogen or halogen, hydroxy, C 1-4 alkoxy, phenyl-C 1-3 alkoxy or C 1-6 alkyl or -NR 7 R 8 or -CO 7 R 7 R 8 (wherein R 7 and R 8, which may be the same or different, each represent hydrogen or C 1-4 alkyl or C 3-4 alkenyl or together with the nitrogen atom to which they are attached form a saturated 5- to 7-membered ring); n represents the number 1, 2 or 3; 20 and A-B represent the group CH-CH 2 or C = CH; and physiologically acceptable salts and solvates thereof.

Der er nu blevet fundet en hidtil ukendt klasse af forbindelser, som adskiller sig strukturelt fra de, der tidligere er beskrevet, idet forbindelserne ifølge den foreliggende op-25 findelse er lactamer, som i modsætning til de fra DE offentliggørelsesskrift nr. 3.740.352 kendte forbindelser har en plan ringstruktur og derfor bærer methylimidazolgruppen i en fikseret orientering, og idet forbindelserne ifølge den foreliggende opfindelse mangler de kendte forbindelsers 30 asymmetriske center ved A (se formlen ovenfor). Forbindelserne ifølge opfindelsen er potente antagonister til 5-HT-virk-ningen ved 5-HT3-receptorer og udviser en forøget virknings-varighed i forhold til de kendte forbindelser.There has now been found a novel class of compounds which differ structurally from those previously described, the compounds of the present invention being lactams which, in contrast to those known from DE Publication No. 3,740,352. compounds have a planar ring structure and therefore carry the methylimidazole group in a fixed orientation, and the compounds of the present invention lack the asymmetric center of the known compounds at A (see formula above). The compounds of the invention are potent antagonists of the 5-HT action at 5-HT 3 receptors and exhibit an increased duration of action over the known compounds.

Den foreliggende opfindelse angår substituerede (imidazol-4-35 yl)methylpyrido-, og -azepino-, indolonderivater med den , almene formel (I): i 3 DK 169922 B1The present invention relates to substituted (imidazol-4-35 yl) methylpyrido, and -azepino, indolone derivatives of the general formula (I):

OISLAND

Q. y-N^lm ΓΪνγ (i) Q R1 hvor Im betegner en imidazolylgruppe med formlen: V=( eller V=( n^/nh hn^n R1 betegner hydrogen, C1.4-alkyl (fx methyl eller isopropyl), 5 C3_4-alkynyl (fx prop-2-ynyl) eller C4.6-cycloalkylmethyl (fx cyclopentylmethyl); R4 betegner Cx.4-alkyl (fx methyl eller n-propyl); Y betegner CH=CH eller (CH2)n, hvor n betegner tallet 2 eller 3; 10 Q betegner halogen (fx fluor eller brom), hydroxy, phenyl-Ci.3-alkoxy (fx phenylmethoxy) , Cx.3-alkyl (fx methyl) eller cyano; Q' betegner hydrogen eller fluor; og fysiologisk acceptable salte og solvater deraf.Q. yN ^ 1m ΓΪνγ (i) Q R1 where Im represents an imidazolyl group of the formula: V = (or V = (n ^ / nh hn ^ n R1 represents hydrogen, C1-4 alkyl (e.g. methyl or isopropyl), 5) C3-4 alkynyl (e.g. prop-2-ynyl) or C4.6 cycloalkylmethyl (e.g. cyclopentylmethyl); R4 represents Cx4 alkyl (e.g. methyl or n-propyl); Y represents CH = CH or (CH2) n where n represents the number 2 or 3; Q represents halogen (e.g. fluorine or bromine), hydroxy, phenylC1-3 alkoxy (e.g. phenylmethoxy), Cx3 alkyl (e.g. methyl) or cyano; Q 'represents hydrogen or fluorine and physiologically acceptable salts and solvates thereof.

15 Egnede fysiologisk acceptable salte af forbindelser med formlen (I) omfatter syreadditionssalte dannet med organiske eller uorganiske syrer, fx hydrochlorider, hydrobromider, sulfater, alkyl- eller arylsulfonater (fx methansulfonater eller p-toluensulfonater), phosphater, acetater, citrater, 20 succinater, tartrater, fumarater og maleater. Solvaterne kan fx være hydrater.Suitable physiologically acceptable salts of compounds of formula (I) include acid addition salts formed with organic or inorganic acids, e.g., hydrochlorides, hydrobromides, sulfates, alkyl or arylsulfonates (e.g., methanesulfonates or p-toluenesulfonates), phosphates, acetates, citrates, succinates, tartrates, fumarates and maleate. For example, the solvates may be hydrates.

Opfindelsen omfatter også alle optiske isomerer af forbindelser med formlen (I) og blandinger deraf herunder racemiske 4 DK 169922 B1 blandinger deraf, og alle geometriske isomerer af forbindelser med formlen (I). *The invention also encompasses all optical isomers of compounds of formula (I) and mixtures thereof including racemic mixtures thereof, and all geometric isomers of compounds of formula (I). *

Med henvisning til den almene formel (I) kan alkyl være lige-kædet eller forgrenet, fx methyl, ethyl, n-propyl, prop-2-yl, 5 n-butyl, but-2-yl eller 2-methylprop-2-yl. Halogen kan fx være fluor, chlor eller brom.Referring to the general formula (I), alkyl may be straight-chain or branched, e.g., methyl, ethyl, n-propyl, prop-2-yl, n-butyl, but-2-yl or 2-methylprop-2- yl. Halogen may be, for example, fluorine, chlorine or bromine.

Substituenten Q' kan sidde i indolgruppens a-, b-, eller c-stilling. Når Q' er fluor, sidder Q' fortrinsvis i a-stil-1ingen.The substituent Q 'can sit in the indole group a, b, or c position. When Q 'is fluorine, Q' is preferably in the α-position.

e A / b· ·_· I I i c· · · w 7 Vxe A / b · · _ · I I i c · · · w 7 Vx

d Id I

10 En foretrukken klasse af forbindelser med formlen (I) er den, hvor R4 betegner methyl.A preferred class of compounds of formula (I) is that wherein R 4 represents methyl.

En anden foretrukken klasse af forbindelser med formlen (I) er den, hvor Q betegner fluor.Another preferred class of compounds of formula (I) is that wherein Q is fluorine.

Endnu en foretrukken klasse af forbindelser med formlen (I) 15 er den, hvor Y betegner (CH2)2.Yet another preferred class of compounds of formula (I) is that wherein Y is (CH 2) 2.

En yderligere foretrukken klasse af forbindelser med formlen (I) er den, hvor Q' betegner hydrogen. Når Q' betegner fluor, betegner Q især halogen (fx fluor).A further preferred class of compounds of formula (I) is that wherein Q 'represents hydrogen. When Q 'denotes fluorine, Q denotes especially halogen (e.g., fluorine).

Inden for de ovenfor foretrukne og særligt foretrukne grupper 20 af forbindelser er en særlig vigtig gruppe af forbindelser den, hvor Y betegner (CH2)2, og Q' betegner hydrogen.Within the above preferred and particularly preferred groups 20 of compounds, a particularly important group of compounds is that wherein Y represents (CH 2) 2 and Q 'represents hydrogen.

Foretrukne forbindelser ifølge opfindelsen er: 6-Fluor-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-lH-imidazol- 4-yl)methyl]-lH-pyrido[4,3-b]indol-l-on; 5 DK 169922 B1 2.3.4.5- tetrahydro-5,6-dimethyl-2 - [(5 -methyl-IH-imidazol- 4 -yl)-methyl]-lH-pyrido[4,3-b]indol-l-on; 6,9-difluor-2,3,4,5-tetrahydro-5-methyl-2 -[(5-methyl-1H-imidazol-4-yl)methyl]-lH-pyrido[4,3- b] indol-1-on; 5 6-fluor-2,3,4,5-tetrahydro-2-[(5-methyl-IH-imidazol-4-yl)-methyl]-5-(2-propynyl)-IH-pyrido[4,3 -b] indol-1-on; 2.3.4.5- tetrahydro-5-methyl-2-[(5-methyl-lH-imidazol-4-yl)-methyl]-1-oxo-lH-pyrido[4,3-b]indol-6-carbonitril; og fysiologisk acceptable salte og solvater deraf.Preferred compounds of the invention are: 6-Fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4.3 b] indol-l-one; 2,3,4,5-tetrahydro-5,6-dimethyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indole-1- one; 6,9-difluoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indole -1-one; 6-Fluoro-2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -5- (2-propynyl) -1H-pyrido [4.3 -b] indol-1-one; 2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1-oxo-1H-pyrido [4,3-b] indole-6-carbonitrile; and physiologically acceptable salts and solvates thereof.

10 Den potente og selektive 5-HT-antagonisme ved 5-HT3-recep-torer, der udvises af forbindelserne ifølge opfindelsen, er blevet påvist ved deres evne til at inhibere 3-(5-methyl-IH-imidazol-4-yl) -1- [1- (methyl-t3) -lH-indol-3-yl] -1-propanon-binding i entorhinale cortexhomogenater fra rotter (ifølge 15 den generelle fremgangsmåde beskrevet af G. Kilpatrick et al. i Nature, 1987, 330. 746), og/eller ved deres evne til at inhibere den 5-HT-inducerede depolarisering af isolerede . vagusnervepræparater fra rotter.The potent and selective 5-HT antagonism of 5-HT 3 receptors exhibited by the compounds of the invention has been demonstrated by their ability to inhibit 3- (5-methyl-1H-imidazol-4-yl) -1- [1- (methyl-t3) -1H-indol-3-yl] -1-propanone binding in entorhinal cortex homogenates of rats (according to the general procedure described by G. Kilpatrick et al. In Nature, 1987, 330. 746), and / or by their ability to inhibit the 5-HT-induced depolarization of isolated. vagus nerve preparations from rats.

Visse forbindelser ifølge opfindelsen besidder foruden deres 20 aktivitet som potente og selektive 5-HT-antagonister ved 5-HT3-receptorer fordelen med en forlænget virkningsvarighed.Certain compounds of the invention, in addition to their activity as potent and selective 5-HT antagonists at 5-HT3 receptors, have the advantage of an extended duration of action.

Virkningsvarigheden af forbindelserne ifølge den foreliggende opfindelse kan kvantificeres ved bestemmelse af virkningen af forbindelserne på 5-HT Bezold-Jarisch(B-J)-refleksen. B-J-25 refleksen er den reflektoriske nedgang i hjertepuls, som kan observeres i pattedyr efter aktivering med 5-HT af receptorer i hjerteregionen.The duration of action of the compounds of the present invention can be quantified by determining the effect of the compounds on the 5-HT Bezold-Jarisch (B-J) reflex. The B-J-25 reflex is the reflective decline in heart rate that can be observed in mammals after activation with 5-HT by receptors in the heart region.

På katte udføres dette forsøg i henhold til fremgangsmåden beskrevet af A Butler et al. (Br. J. Pharmacol. 94, 397-412 30 (1988)). 2-Methyl-5HT benyttes i stedet for 5-HT hos katte, fordi denne forbindelse virker specifikt ved 5-HT3-receptorer og ikke ved andre 5-HT-receptorundertyper. Forbindelserne ifølge den foreliggende opfindelse blokerer selektivt virkningen af 2-methyl-5-HT ved receptorerne i hjertet.In cats, this experiment is performed according to the method described by A. Butler et al. (Br. J. Pharmacol. 94, 397-412 (1988)). 2-Methyl-5HT is used in place of 5-HT in cats because this compound acts specifically on 5-HT3 receptors and not on other 5-HT receptor subtypes. The compounds of the present invention selectively block the action of 2-methyl-5-HT at the receptors in the heart.

6 DK 169922 B16 DK 169922 B1

Resultaterne af undersøgelsen kan udtrykkes i fom af virkningsvarighed, specielt i fom af varigheden af DR5 (Dur/DR5) . DR5 er den omtrentlige dosis, der kræves for at give en 5-ganges højreforskydning af dosis/respons-kurven 5 overfor 2-methyl-5-HT, og varigheden af DR5 er det tidsrum, i hvilket en sådan flytning opretholdes. Dvs., at store Dur/DR5-værdier indicerer, at forbindelserne har lang virkningsvarighed.The results of the study can be expressed in terms of duration of action, especially in terms of duration of DR5 (Dur / DR5). DR5 is the approximate dose required to give a 5-fold right-shift of dose-response curve 5 to 2-methyl-5-HT, and the duration of DR5 is the length of time during which such movement is maintained. That is, large Dur / DR5 values indicate that the compounds have a long duration of action.

oisland

' 1 CHS'1 CHS

itWITW

—γ N^NH—Γ N + NH

Q Me DE 3.740.352 Forbindelser ifølge Q Q’ Y Z Dur/DR5 (min) opfindelsen Dosis = 1/ig/kg i.v.Q Me DE 3,740,352 Compounds of Q Q 'Y Z Dur / DR5 (min) invention Dose = 1 µg / kg i.v.

10 Eksempel nr. Eksempel nr.Example No. Example No.

10 c-F H -(CH2)2- C 8 23 b-F H -(CH2)2- C 3 1 d-F H -(CH2)2- N 52 12 HH -(CH2)3- C 46; 0a 7 d-F H -(CH2)3- N 51b; >54aC-F H - (CH2) 2- C 8 23 b-F H - (CH2) 2- C 3 1 d-F H - (CH2) 2- N 52 12 HH - (CH2) 3- C 46; 0a 7 d-F H - (CH 2) 3- N 51b; > 54a

N/AREACH

14 d-F H -CH-CH- N >125°14 d-F H -CH-CH- N> 125 °

15 N/A15 N / A

6 d-F F -(CH2)2- N 80a a = dosis på 3 mg/kg intradermalt b = middelværdi af to værdier, 13 og 90 c = dosis på 10 mg/kg intravenøst N/A = findes ikke, idet Y ikke må være -CH=CH- i DE 3.740.352 20 Som det fremgår af ovenstående tabel udviser forbindelserne - ifølge opfindelsen klart længere virkningsvarigheder end de 7 DK 169922 B1 fra DE offentliggørelsesskrift nr. 3.740.352 kendte forbindelser samt andre ketoner med Y * -CH=CH- eller Q' = F.6 dF F - (CH2) 2- N 80a a = dose of 3 mg / kg intradermal b = mean of two values, 13 and 90 c = dose of 10 mg / kg intravenous N / A = not present, since Y must not as -CH = CH- in DE 3,740,352 20 As can be seen from the above table, the compounds - according to the invention clearly exhibit longer duration of action than the known compounds and other ketones with Y * -CH = CH- or Q '= F.

6- Fluor- 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-IH-imidazol- 4-yl)methyl]-lH-pyrido[4,3-b]indol-l-on og fysiologisk accep-5 table salte og solvater deraf er en særligt foretrukken forbindelse med hensyn til både dens potens og virkningsvarighed. Foretrukne salte af denne forbindelse er hydrochloridet, maleatet og benzoatet.6- Fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indole-1 -on and physiologically acceptable salts and solvates thereof are a particularly preferred compound in both its potency and duration of action. Preferred salts of this compound are the hydrochloride, maleate and benzoate.

Forbindelser med formlen (I), som antagoniserer 5-HT's virk-10 ning ved 5-HT3-receptorer er nyttige til behandling af tilstande såsom psykotiske sygdomme (fx skizofreni og mania); angst; og kvalme og opkastning, især i forbindelse med cancerkemoterapi og radioterapi. Forbindelser med formlen (I) er også nyttige til behandling af gastrisk stasis; gastroin-15 testinale dysfunktionssymptomer som forekommer i forbindelse med dyspepsia, mavesår, refluks oesophagitis, flatulens og irritabelt tamsyndrom; migræne; obesitas og tilstande såsom bulimi; og smerte. Forbindelser med fomlen (I) kan også anvendes til behandling af lægemiddelafhængighed og stofmis-20 brug, depression og dementia og andre kognitive sygdomme.Compounds of formula (I) which antagonize the action of 5-HT at 5-HT 3 receptors are useful in the treatment of conditions such as psychotic disorders (e.g., schizophrenia and mania); anxiety; and nausea and vomiting, especially in the context of cancer chemotherapy and radiotherapy. Compounds of formula (I) are also useful in the treatment of gastric stasis; gastrointestinal dysfunction symptoms associated with dyspepsia, ulcer, reflux oesophagitis, flatulence and irritable bowel syndrome; migraine; obesity and conditions such as bulimia; and pain. Compounds with fomel (I) can also be used to treat drug dependence and substance abuse, depression and dementia and other cognitive disorders.

Opfindelsen muliggør en metode til behandling af mennesker eller dyr, der lider af en psykotisk sygdom såsom skizofreni eller mania; eller af angst; kvalme eller opkastning; gastrisk statis; gastrointestinale dysfunktionssymptomer såsom 25 dyspepsia, reflux oesophagitis, mavesår, flatulens og irritabelt tamsyndrom; migræne; obesitas og tilstande såsom bulimi; smerte; lægemiddelafhængighed eller stofmisbrug; depression; eller dementia eller andre kognitive sygdomme, hvilken metode omfatter administration af en virksom mængde af en 30 forbindelse med fomlen (I) eller et fysiologisk acceptabelt salt eller solvat deraf.The invention enables a method of treating humans or animals suffering from a psychotic illness such as schizophrenia or mania; or of anxiety; nausea or vomiting; gastric statis; gastrointestinal dysfunction symptoms such as dyspepsia, reflux oesophagitis, ulcers, flatulence and irritable bowel syndrome; migraine; obesity and conditions such as bulimia; pain; drug addiction or substance abuse; depression; or dementia or other cognitive disorders, the method comprising administering an effective amount of a compound to the pharynx (I) or a physiologically acceptable salt or solvate thereof.

Opfindelsen angår således også et farmaceutisk præparat, som omfatter mindst én forbindelse valgt blandt forbindelser med fomlen (I) og fysiologisk acceptable salte og solvater deraf 8 * DK 169922 B1 (fx hydrater) sammen med mindst ét fysiologisk acceptabelt bærestof eller hjælpestof, til anvendelse i human- eller veterinærmedicin og formuleret til administration ad en hvilken som helst egnet vej.Thus, the invention also relates to a pharmaceutical composition comprising at least one compound selected from compounds of the formula (I) and physiologically acceptable salts and solvates thereof 8 together with at least one physiologically acceptable carrier or excipient for use in human or veterinary medicine and formulated for administration by any suitable route.

5 Sådanne præparater kan formuleres på konventionel måde ved at anvende ét eller flere fysiologisk acceptable bærerstoffer og/eller hjælpestoffer.Such compositions may be formulated in conventional manner using one or more physiologically acceptable carriers and / or adjuvants.

Forbindelserne ifølge opfindelsen kan således formuleres til oral, bukkal, parenteral eller rektal administration eller i 10 en form, der er egnet til administration ved inhalation eller insufflation (enten gennem munden eller næsen).Thus, the compounds of the invention may be formulated for oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose).

Til oral administration kan de farmaceutiske præparater foreligge i form af fx tabletter eller kapsler fremstillet på konventionel måde med farmaceutisk acceptable hjælpestoffer 15 såsom bindemidler (fx prægelatineret majsstivelse, polyvinyl-pyrrolidon eller hydroxypropylmethylcellulose); fyldemidler (fx lactose, mikrokrystallinsk cellulose eller calciumhydro-genphosphat); glittemidler (fx magnesiumstearat, talkum eller siliciumdioxid); sprængemidler (fx kartoffelstivelse eller 20 natriumstivelsesglycollat); eller befugtningsmidler (fx natriumlaurylsulfat). Tabletterne kan overtrækkes ved metoder, der er kendte inden for området. Flydende præparater til oral administration kan foreligge i form af fx opløsninger, syrupper eller suspensioner, eller de kan foreligge som et 25 tørprodukt til rekonstitution med vand eller andet egnet vehikel før anvendelse. Sådanne flydende præparater kan fremstilles på konventionel måde med farmaceutisk acceptable tilsætningsstoffer såsom suspenderingsmidler (fx sorbitolsyrup, cellulosederivater eller hydrogenerede spiselige fedtstof-30 fer); emulgeringsmidler (fx lecithin eller akacie); ikke-vandige vehikler (fx mandelolie, olieagtige estere, ethyl-alkohol eller fraktionerede vegetabilske olier); og konserveringsmidler (fx methyl eller propyl-p-hydroxybenzoater eller sorbinsyre). Præparaterne kan om nødvendigt også indeholde 9 DK 169922 B1 buffersalte, aromagivende, farvegivende stoffer og sødemidler.For oral administration, the pharmaceutical compositions may be in the form of, for example, tablets or capsules prepared in a conventional manner with pharmaceutically acceptable excipients such as binders (e.g. pregelatinized corn starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated by methods known in the art. Liquid preparations for oral administration may be in the form of, for example, solutions, acid groups or suspensions, or they may be available as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid compositions may be prepared in a conventional manner with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifiers (e.g., lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). The compositions may also contain, if necessary, 9 DK 169922 B1 buffer salts, flavoring, coloring agents and sweeteners.

Præparater til oral administration kan hensigtsmæssigt formuleres til opnåelse af kontrolleret afgift af den aktive 5 forbindelse.Compositions for oral administration may conveniently be formulated to obtain controlled release of the active compound.

Til bukkal administration kan præparaterne foreligge i form af tabletter eller pastiller, der er formuleret på konventionel måde.For buccal administration, the compositions may be in the form of tablets or lozenges formulated in conventional manner.

Forbindelserne ifølge opfindelsen kan formuleres til paren-10 teral administration ved bolusinjektion eller kontinuerlig infusion. Injektionsformuleringerne kan foreligge i enheds-doseringsform fx i ampuller eller i flerdosisbeholdere, med et tilsat konserveringsmiddel. Præparaterne kan foreligge i form af suspensioner, opløsninger eller emulsioner i olie-15 agtige eller vandige vehikler og kan indeholde formulerings-midler såsom suspenderings-, stabiliserings- og/eller disperseringsmidler. Alternativt kan den aktive bestanddel foreligge i pulverform til rekonstitution før anvendelsen med et egnet vehikel, fx sterilt, pyrogenfrit vand.The compounds of the invention may be formulated for parenteral administration by bolus injection or continuous infusion. The injection formulations may be in unit dosage form, for example, in ampoules or in multi-dose containers, with an added preservative. The compositions may be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulation agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution prior to use with a suitable vehicle, e.g., sterile, pyrogen-free water.

20 Forbindelserne ifølge opfindelsen kan også formuleres i rektale præparater såsom suppositorier eller retentionsklys-tre, fx indeholdende konventionelle suppositoriegrundmasser såsom kakaosmør eller andre glycerider.The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention clays, for example containing conventional suppository matrixes such as cocoa butter or other glycerides.

Ud over de ovenfor beskrevne præparater kan forbindelserne 25 ifølge opfindelsen også formuleres som depotpræparater. Sådanne langtidsvirkende præparater kan administreres ved implantation (fx subkutant eller intramuskulært) eller ved intramuskulær injektion. Forbindelserne ifølge opfindelsen kan således fx formuleres med egnede polymere eller hydrofobe 30 materialer (fx som emulsion i en acceptabel olie) eller ionbytterharpiks, eller som tungtopløselige derivater, fx som et tungtopløseligt salt.In addition to the compositions described above, the compounds of the invention can also be formulated as depot preparations. Such long-acting preparations may be administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, the compounds of the invention may, for example, be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resin, or as heavy-soluble derivatives, e.g., as a heavy-soluble salt.

10 DK 169922 B110 DK 169922 B1

Til administration ved inhalation afgives forbindelserne ifølge opfindelsen hensigtsmæssigt i form af en aerosolspray a fra overtryksbeholdere eller en nebulisator under anvendelse af en egnet drivgas, fx dichlordifluormethan, trichlorfluor-5 methan, dichlortetrafluorethan, carbondioxid eller en anden egnet gas. Når en overtryksaerosol anvendes kan doseringen bestemmes ved hjælp af en ventil, der er beregnet til at afgive en afmålt mængde. Kapsler og patroner af fx gelatine til anvendelse i en inhalator eller insufflator kan formu-10 leres indeholdende en pulverblanding af en forbindelse ifølge opfindelsen og en egnet pulvermasse såsom lactose eller stivelse.For administration by inhalation, the compounds of the invention are suitably dispensed in the form of an aerosol spray a from pressure vessels or a nebulizer using a suitable propellant gas, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. When an overpressure aerosol is used, the dosage can be determined by a valve designed to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated containing a powder mixture of a compound of the invention and a suitable powder mass such as lactose or starch.

Til intranasal administration kan forbindelserne ifølge opfindelsen formuleres som opløsninger til administration via 15 en egnet måle- eller enhedsdosisanordning eller alternativt som en pulverblanding med et egnet bærerstof til administration under anvendelse af en egnet afgivelsesanordning.For intranasal administration, the compounds of the invention can be formulated as solutions for administration via a suitable measuring or unit dose device or alternatively as a powder mixture with a suitable carrier for administration using a suitable delivery device.

Forbindelserne med formlen (I) kan også administreres i kombination med andre terapeutiske midler. Ved behandling af 20 gastrisk statis, gastrointestinale dysfunktionssymptomer og kvalme og opkastning kan forbindelserne med formlen (I) således fx administreres i kombination med antisekretoriske midler såsom histamin H2-receptorantagonister (fx ranitidin, sufotidin, cimetidin, famotidin, nizatidin eller roxatidin) 25 eller H+K+ATPase-inhibitorer (fx omeprazol) . Ved behandlingen af kvalme og opkastning kan forbindelser med formlen (I) også administreres i kombination med dexamethason eller en cyclo-oxygenaseinhibitor såsom piroxicam.The compounds of formula (I) may also be administered in combination with other therapeutic agents. Thus, in the treatment of gastric stasis, gastrointestinal dysfunction symptoms and nausea and vomiting, the compounds of formula (I) may be administered, for example, in combination with antisecretory agents such as histamine H2 receptor antagonists (e.g. ranitidine, sufotidine, cimetidine, famotidine, nizatidine or roxidine). + K + ATPase inhibitors (e.g., omeprazole). In the treatment of nausea and vomiting, compounds of formula (I) may also be administered in combination with dexamethasone or a cyclooxygenase inhibitor such as piroxicam.

En foretrukken dosis af forbindelserne ifølge opfindelsen til 30 administration til mennesker (med en legemsvægt på ca. 70 kg) er 0,001-100 mg, især 0,01-50 mg, fortrinsvis 0,1-20 mg af den aktive bestanddel pr. enhedsdosis udtrykt som vægten af fri base, hvilken dosis kan administreres fx 1-4 gange dagligt. Det kan selvfølgelig være nødvendigt at lave rutineæn-35 dringer, hvad angår doseringen, afhængig af patientens alder 11 DK 169922 B1 og tilstand. Doseringen afhænger også af administrations-vejen.A preferred dose of the compounds of the invention for administration to humans (with a body weight of about 70 kg) is 0.001-100 mg, especially 0.01-50 mg, preferably 0.1-20 mg of the active ingredient per day. unit dose expressed as the weight of free base, which dose can be administered eg 1-4 times daily. Of course, it may be necessary to make routine changes regarding the dosage, depending on the patient's age and condition. The dosage also depends on the route of administration.

Forbindelser med den almene formel (I) og fysiologisk acceptable salte og solvater deraf kan fremstilles ved de almene 5 fremstillingsmåder, der er beskrevet i det følgende. I den efterfølgende beskrivelse har R1, Y, Q, Q' og Im samme betydning som anført for forbindelser med formlen (I), medmindre andet er anført.Compounds of general formula (I) and physiologically acceptable salts and solvates thereof can be prepared by the general modes of preparation described below. In the following description, R1, Y, Q, Q 'and Im have the same meaning as stated for compounds of formula (I), unless otherwise stated.

Ifølge den første fremgangsmådevariant (A) kan en forbindelse 10 med den almene formel (I) fremstilles ifølge opfindelsen ved, at en forbindelse med formlen (II):According to the first process variant (A), a compound 10 of the general formula (I) can be prepared according to the invention by a compound of formula (II):

OISLAND

>NH> NH

r*YVr * YV

Q 'R1 alkyleres med en forbindelse med formlen (III): X-Im (III) hvor Q, Q', R1 og Y har de ovenfor anførte betydninger eller 15 et beskyttet derivat deraf, hvor Im har de ovenfor anførte betydninger og X betegner -CH2L, og L betegner en fraspaltelig enhed såsom halogen (fx chlor, brom eller iod) eller acyloxy (fx trifluoracetyloxy eller acetoxy), eller sulfonyl-oxy (fx trifluormethansulfonyloxy, p-toluensulfonyloxy eller 20 methansulfonyloxy), og omsætningen sker i nærværelse af en base; eller X betegner -CH20H, og omsætningen udføres i nærværelse af en syre ved en forhøjet temperatur efterfulgt, om nødvendigt, af fjernelse af en hvilken som helst beskyttelsesgruppe.Q 'R1 is alkylated with a compound of formula (III): X-Im (III) wherein Q, Q', R1 and Y have the above meanings or a protected derivative thereof, wherein Im has the above meanings and X represents -CH2L, and L represents a leaving group such as halogen (e.g., chlorine, bromine or iodine) or acyloxy (e.g., trifluoroacetyloxy or acetoxy), or sulfonyl-oxy (e.g., trifluoromethanesulfonyloxy, p-toluenesulfonyloxy or methanesulfonyloxy), and the reaction occurs near a base; or X represents -CH 2 OH and the reaction is carried out in the presence of an acid at an elevated temperature followed, if necessary, by the removal of any protecting group.

12 DK 169922 B112 DK 169922 B1

Ifølge én udførelsesform (a) af fremgangsmåden (A) udføres omsætningen med en forbindelse med formlen (III), hvor X ? betegner -CH2L, og L især er halogen (fx chlor). Omsætningen kan udføres i et inert opløsningsmiddel såsom ether (fx di-5 methoxyethan, diglym eller tetrahydrofuran), et substitueret amid (fx dimethyl formamid eller N-methylpyrrolidon), et aromatisk carbonhydrid (fx toluen), en keton (fx acetone) eller dime thy 1 sul f oxid ved en temperatur på mellem omgivelses temperatur og 100°C i nærværelse af en base. Egnede baser omfatter 10 alkalimetalhydrider (fx natriumhydrid), alkalimetalcarbonater (fx natriumcarbonat), alkalimetalamider (fx natriumamid), alkalimetalalkoxider (fx kalium t-butoxid) eller alkalimetal-hydroxider (fx natrium- eller kaliumhydroxid).According to one embodiment (a) of process (A), the reaction is carried out with a compound of formula (III) wherein X? represents -CH 2 L, and L in particular is halogen (e.g., chlorine). The reaction may be carried out in an inert solvent such as ether (e.g., dimethoxyethane, diglym or tetrahydrofuran), a substituted amide (e.g., dimethyl formamide or N-methylpyrrolidone), an aromatic hydrocarbon (e.g., toluene), a ketone (e.g., acetone), or dime. thy 1 sul f oxide at a temperature of between ambient temperature and 100 ° C in the presence of a base. Suitable bases include 10 alkali metal hydrides (e.g., sodium hydride), alkali metal carbonates (e.g., sodium carbonate), alkali metal amides (e.g., sodium amide), alkali metal alkoxides (e.g., potassium t-butoxide), or alkali metal hydroxides (e.g., sodium or potassium hydroxide).

Ifølge en anden udførelsesform (b) af fremgangsmåden (A) 15 udføres omsætningen med en forbindelse med formlen (III), hvor X betegner -CH20H, i nærværelse af en syre. Syren kan fx være en stærk mineralsyre (fx saltsyre) eller en hydrocarbyl-sulfonsyre (fx p-toluensulfonsyre). Omsætningen udføres hensigtsmæssigt i et højtkogende polært opløsningsmiddel 20 såsom N-methylpyrrolidinon eller dimethylacetamid ved en forhøjet temperatur, fx i området 100-200°C. Alternativt kan omsætningen hensigtsmæssigt udføres i vand eller en alkohol (fx isopropanol) ved opløsningsmidlets tilbagesvalingstemperatur.According to another embodiment (b) of process (A), the reaction is carried out with a compound of formula (III) wherein X is -CH 2 OH, in the presence of an acid. The acid may be, for example, a strong mineral acid (e.g. hydrochloric acid) or a hydrocarbyl sulfonic acid (e.g. p-toluenesulfonic acid). The reaction is conveniently carried out in a high boiling polar solvent 20 such as N-methylpyrrolidinone or dimethylacetamide at an elevated temperature, for example in the range 100-200 ° C. Alternatively, the reaction may conveniently be carried out in water or an alcohol (e.g., isopropanol) at the reflux temperature of the solvent.

25 Ifølge den anden fremgangsmådevariant (B) kan en forbindelse med den almene formel (I) ifølge opfindelsen omdannes til en anden forbindelse med formlen (I) ved anvendelse af konventionelle teknikker. Sådanne konventionelle teknikker omfatter hydrogenering, alkylering og acylering om nødvendigt under 30 anvendelse af beskyttelse og afbeskyttelse.According to the second process variant (B), a compound of the general formula (I) according to the invention can be converted to another compound of the formula (I) using conventional techniques. Such conventional techniques include hydrogenation, alkylation and acylation if necessary using protection and deprotection.

Ifølge én udførelsesform af omdannelsesmetoden (B) kan en forbindelse med formlen (I), hvor Y betegner (CH2)2 således fremstilles ved hydrogenering af den tilsvarende forbindelse med formlen (I), hvor Y betegner CH=CH. Hydrogenering kan 35 også anvendes til fremstilling af en forbindelse med formlen 13 DK 169922 B1 (I) , hvor Q betegner hydroxyl ud fra den tilsvarende forbindelse med formlen (I), hvor Q betegner phenylmethoxy. Hydrogenering kan også anvendes til omdannelse af en alkenyl-eller alkynylsubstituent til en alkylsubstituent eller en 5 alkynylsubstituent til en alkenylsubstituent. Hydrogenering ifølge den almene fremgangsmåde (B) kan udføres under anvendelse af konventionelle metoder, fx ved anvendelse af hydrogen i nærværelse af en ædelmetalkatalysator (palladium, Raney-nikkel, platin eller rhodium). Katalysatoren kan fx 10 være båret på trækul eller aluminiumoxid, eller alternativt kan der anvendes en homogen katalysator såsom tris(triphenyl-phosphin)rhodiumchlorid. Hydrogenering udføres almindeligvis i et opløsningsmiddel såsom en alkohol (fx methanol eller ethanol), en ether (fx dioxan) eller en ester (fx ethylace-15 tat) eller i en blanding af en alkohol og enten et carbon-hydrid (fx toluen) eller et halogeneret carbonhydrid (fx dichlormethan) ved en temperatur i området fra -20°C til +100°C og ved et tryk på fra 1 til 10 atmosfære.Thus, according to one embodiment of the conversion method (B), a compound of formula (I) wherein Y represents (CH 2) 2 can be prepared by hydrogenating the corresponding compound of formula (I) where Y represents CH = CH. Hydrogenation can also be used to prepare a compound of Formula 13 where Q represents hydroxyl from the corresponding compound of Formula (I) where Q represents phenylmethoxy. Hydrogenation can also be used to convert an alkenyl or alkynyl substituent to an alkyl substituent or an alkynyl substituent to an alkenyl substituent. Hydrogenation according to the general process (B) can be carried out using conventional methods, for example using hydrogen in the presence of a precious metal catalyst (palladium, Raney nickel, platinum or rhodium). For example, the catalyst may be supported on charcoal or alumina, or alternatively, a homogeneous catalyst such as tris (triphenylphosphine) rhodium chloride may be used. Hydrogenation is generally carried out in a solvent such as an alcohol (e.g., methanol or ethanol), an ether (e.g., dioxane) or an ester (e.g., ethyl acetate), or in a mixture of an alcohol and either a hydrocarbon (e.g., toluene) or a halogenated hydrocarbon (e.g., dichloromethane) at a temperature in the range of -20 ° C to + 100 ° C and at a pressure of from 1 to 10 atmospheres.

Udtrykket "alkylering" ifølge den almene fremgangsmåde (B) 20 omfatter indføring af grupper såsom cycloalkyl, alkenyl eller phenalkyl.The term "alkylation" according to the general process (B) 20 includes the introduction of groups such as cycloalkyl, alkenyl or phenalkyl.

En forbindelse med formlen (I) , hvor R1 betegner C^-alkyl, C3_4-alkynyl eller C4.6-cycloalkyl-methyl, kan således fx fremstilles ved alkylering af en forbindelse med formlen (I), 25 hvor R1 betegner hydrogen, under anvendelse af konventionelle metoder, fx som beskrevet i EP 242973. Omsætningerne kan således udføres under anvendelse af egnede alkyleringsmidler med formlen R12Z (hvor R12 er den gruppe, der skal indføres, og Z er en fraspaltelig enhed), fortrinsvis i nærværelse af 30 en base.Thus, a compound of formula (I) wherein R 1 represents C 1-4 alkyl, C 3-4 alkynyl or C 4-6 cycloalkyl methyl may be prepared, for example, by alkylating a compound of formula (I) wherein R 1 represents hydrogen, under The use of conventional methods, for example as described in EP 242973. Thus, the reactions can be carried out using suitable alkylating agents of formula R12Z (where R12 is the group to be introduced and Z is a leaving group), preferably in the presence of a base. .

Forbindelser med formlen (I) kan også fremstilles ud fra andre forbindelser med formlen (I) ved konventionelle omdannelsesreaktioner mellem funktionelle grupper eller ved en række af sådanne reaktioner.Compounds of formula (I) may also be prepared from other compounds of formula (I) by conventional conversion reactions between functional groups or by a variety of such reactions.

14 DK 169922 B114 DK 169922 B1

Det er klart, at ved de ovennævnte omdannelser kan det for at undgå uønskede sidereaktioner være nødvendigt eller ønskeligt at beskytte en hvilken som helst følsom gruppe i den omtalte forbindelses molekyle. Fx kan det være nødvendigt at beskytte 5 indol- og/eller imidazolnitrogenatomer, fx med arylmethyl (fx trityl), arylmethoxymethyl (fx phenylmethoxymethyl) , alkyl (fx t-butyl), alkoxymethyl (fx methoxymethyl), acyl (fx benzyloxycarbonyl) eller sulfonyl (fx N,N-dimethyl-aminosul-fonyl eller p-toluensulfonyl). Når Q betegner hydroxyl, kan 10 det være nødvendigt at beskytte hydroxylgruppen, fx med arylmethyl (fx benzyl eller trityl).It is to be understood that in the aforementioned conversions, to avoid undesired side reactions, it may be necessary or desirable to protect any sensitive group in the molecule of said compound. For example, it may be necessary to protect 5 indole and / or imidazole nitrogen atoms, for example with arylmethyl (e.g. trityl), arylmethoxymethyl (e.g. phenylmethoxymethyl), alkyl (e.g. t-butyl), alkoxymethyl (e.g. methoxymethyl), acyl (e.g. benzyloxycarbonyl) (e.g., N, N-dimethylaminosulfonyl or p-toluenesulfonyl). When Q represents hydroxyl, it may be necessary to protect the hydroxyl group, for example with arylmethyl (e.g. benzyl or trityl).

Ifølge den tredje fremgangsmådevariant (C) ifølge opfindelsen kan en forbindelse med formlen (I) således fremstilles ved fjernelse af eventuelle beskyttelsesgrupper fra en beskyttet 15 form af en forbindelse med formlen (I).Thus, according to the third process variant (C) of the invention, a compound of formula (I) can be prepared by removing any protecting groups from a protected form of a compound of formula (I).

Afbeskyttelse kan udføres under anvendelse af konventionelle teknikker såsom de, der er beskrevet i "Protective Groups in Organic Synthesis" af T. W. Greene (John Wiley and Sons, 1981).Deprotection may be performed using conventional techniques such as those described in "Protective Groups in Organic Synthesis" by T. W. Greene (John Wiley and Sons, 1981).

20 Arylmethoxymethyl som N-beskyttelsesgruppe kan således spaltes ved hydrogenolyse i nærværelse af en katalysator (fx palladium-på-trækul). En tritylgruppe kan spaltes ved syrehydrolyse (fx ved anvendelse af fortyndet saltsyre eller eddikesyre) . En alkoxyalkylgruppe kan fjernes ved at anvende en 25 mineralsyre (fx fortyndet saltsyre eller brombrintesyre). En acylgruppe kan fjernes ved hydrolyse under sure eller basiske betingelser (fx under anvendelse af hydrogenbromid, fortyndet saltsyre eller natriumhydroxid). En sulfonylgruppe kan også fjernes ved basisk eller sur hydrolyse, og en N,N-dimethyl-30 aminosulfonylgruppe kan også fjernes (fx fra et imidazol-nitrogenatom) ved fotolyse. Arylmethyl som OH-beskyttelses-gruppe kan spaltes under sure betingelser (fx med fortyndet eddikesyre, brombrintesyre eller bortribromid) eller ved hydrogenolyse i nærværelse af en katalysator (fx palladium-35 på-trækul).Thus, arylmethoxymethyl as N-protecting group can be cleaved by hydrogenolysis in the presence of a catalyst (e.g., palladium-on-charcoal). A trityl group can be cleaved by acid hydrolysis (e.g., using dilute hydrochloric acid or acetic acid). An alkoxyalkyl group may be removed by using a mineral acid (e.g., dilute hydrochloric or hydrochloric acid). An acyl group can be removed by hydrolysis under acidic or basic conditions (e.g. using hydrogen bromide, dilute hydrochloric acid or sodium hydroxide). A sulfonyl group may also be removed by basic or acidic hydrolysis, and an N, N-dimethylaminosulfonyl group may also be removed (e.g. from an imidazole nitrogen atom) by photolysis. Arylmethyl as the OH protecting group can be cleaved under acidic conditions (e.g., with dilute acetic acid, hydrochloric acid or boron tribromide) or by hydrogenolysis in the presence of a catalyst (e.g., palladium-35 charcoal).

15 DK 169922 B115 DK 169922 B1

Forbindelser med formlen (II), hvor Y betegner (CH2)n, og R1 betegner hydrogen, kan fx fremstilles ved cyklisering af en forbindelse med formlen (IV):For example, compounds of formula (II) wherein Y represents (CH 2) n and R1 represents hydrogen may be prepared by cyclization of a compound of formula (IV):

°WX A° WX A

I jf .NHI cf.NH

ιγλΝΛ'(σΗ2)η (IV)ιγλΝΛ '(σΗ2) η (IV)

Q HQ H

5 hvor X betegner hydrogen eller halogen (fx brom eller iod). Cykliseringen kan udføres under anvendelse af metoder, der er analoge med de, der er beskrevet af H. Iida et al. i J. Orcr. Chem.. 1980, 4£, 2938.Wherein X represents hydrogen or halogen (e.g., bromine or iodine). The cyclization can be performed using methods analogous to those described by H. Iida et al. in J. Orcr. Chem. 1980, £ 4, 2938.

Forbindelser med formlen (II), hvor Y betegner (CH2)n, og R1 10 er forskellig fra hydrogen, kan fremstilles ud fra en forbindelse med formlen (II) , hvor R1 betegner hydrogen, ved konventionelle alkylerings-, acylerings- og sulfonylerings-metoder som fx beskrevet i omdannelsesmetoden (B) ovenfor.Compounds of formula (II) wherein Y represents (CH 2) n and R1 is different from hydrogen can be prepared from a compound of formula (II) wherein R1 represents hydrogen, by conventional alkylation, acylation and sulfonylation processes. methods as described, for example, in the conversion method (B) above.

Forbindelser med formlen (II), hvor Y betegner CH=CH, kan 15 fremstilles ved opvarmning af en forbindelse med formlen (II), hvor Y betegner (CH2)2 eller et beskyttet derivat deraf, med en ædelmetalkatalysator såsom palladium, palladiumoxid, platin eller nikkel ved en temperatur på fx 200-350°C. Katalysatoren kan fx være båret på trækul eller alumi-20 niumoxid, og omsætningen kan eventuelt udføres i nærværelse af et inert opløsningsmiddel såsom aromatisk carbonhydrid (fx p-cymen) eller ethylenglycol.Compounds of formula (II) wherein Y represents CH = CH may be prepared by heating a compound of formula (II) wherein Y represents (CH 2) 2 or a protected derivative thereof, with a precious metal catalyst such as palladium, palladium oxide, platinum or nickel at a temperature of, for example, 200-350 ° C. For example, the catalyst may be supported on charcoal or alumina, and the reaction may optionally be carried out in the presence of an inert solvent such as aromatic hydrocarbon (e.g. p-cymene) or ethylene glycol.

Forbindelser med formlen (IV) kan fx fremstilles ved, at en forbindelse med formlen (V): 16 DK 169922 B1Compounds of formula (IV) can be prepared, for example, by a compound of formula (V): 16 DK 169922 B1

Q· XQ · X

(v) i nh2(v) in nh2

QQ

hvor X har den ovenfor anførte betydning , omsættes med en forbindelse med formlen (VI): 0 /\„ (vi> i—0:¾) 0 5 ved forhøjet temperatur.wherein X has the meaning given above, is reacted with a compound of formula (VI): 0 / \ "(vi> i-0: ¾) 0 5 at elevated temperature.

Forbindelser med formlen (III) og beskyttede derivater deraf er enten kendte eller kan fx fremstilles ved metoder, der er analoge med de, der er beskrevet i EP 242973.Compounds of formula (III) and protected derivatives thereof are either known or can be prepared, for example, by methods analogous to those described in EP 242973.

Forbindelser med formlen (V) og (VI) er enten kendte eller 10 kan fremstilles ud fra kendte forbindelser ved konventionelle metoder.Compounds of formula (V) and (VI) are either known or can be prepared from known compounds by conventional methods.

Isolering af en forbindelse ifølge opfindelsen som et salt, fx et fysiologisk acceptabelt salt, kan, om ønsket, opnås ved at omsætte forbindelsen med formlen (I) i fri baseform med en 15 egnet syre, fortrinsvis i ækvivalent mængde, i et egnet opløsningsmiddel såsom en alkohol (fx ethanol eller methanol) , en vandig alkohol (fx vandig ethanol), et halogeneret carbonhydrid (fx dichlormethan), en ester (fx ethylacetat) eller en ether (fx tetrahydrofuran).Isolation of a compound of the invention as a salt, e.g., a physiologically acceptable salt, can be obtained, if desired, by reacting the compound of formula (I) in free base form with a suitable acid, preferably in equivalent amount, in a suitable solvent such as an alcohol (e.g., ethanol or methanol), an aqueous alcohol (e.g., aqueous ethanol), a halogenated hydrocarbon (e.g., dichloromethane), an ester (e.g., ethyl acetate), or an ether (e.g., tetrahydrofuran).

20 Fysiologisk acceptable salte kan også fremstilles ud fra andre salte, herunder andre fysiologisk acceptable salte, af 17 DK 169922 B1 forbindelsen med formlen (I) under anvendelse af konventionelle metoder.Physiologically acceptable salts may also be prepared from other salts, including other physiologically acceptable salts, of the compound of formula (I) using conventional methods.

Individuelle enantiomerer af forbindelser ifølge opfindelsen kan opnås ved opspaltning af en blanding af enantiomerer (fx 5 en racemisk blanding) under anvendelse af konventionelle metoder, såsom en optisk aktiv opspaltningssyre; se fx "Stereochemistry of Carbon Compounds" af E. L. Eliel (McGraw Hiil, 1962) og "Tables of Resolving Agents" af S. H. Wilen.Individual enantiomers of compounds of the invention can be obtained by cleavage of a mixture of enantiomers (e.g., a racemic mixture) using conventional methods such as an optically active cleavage acid; see, for example, "Stereochemistry of Carbon Compounds" by E. L. Eliel (McGraw Hiil, 1962) and "Tables of Resolving Agents" by S. H. Wilen.

De ovenfor beskrevne fremgangsmåder til fremstilling af 10 forbindelserne ifølge opfindelsen kan anvendes til indføring af de ønskede grupper på et hvilken som helst stadium i den trinvise dannelse af de ønskede forbindelser, og det er klart, at disse metoder kan kombineres på forskellige måder i sådanne flertrinsprocesser. Reaktionssekvensen i en fler-15 trinsproces bør selvfølgelig vælges således, at de anvendte reaktionsbetingelser ikke påvirker de molekylgrupper, som ønskes i slutproduktet.The above-described methods of preparing the compounds of the invention can be used to introduce the desired groups at any stage in the stepwise formation of the desired compounds, and it is clear that these methods can be combined in various ways in such multi-step processes. . Of course, the reaction sequence in a multi-step process should be chosen such that the reaction conditions used do not affect the molecular groups desired in the final product.

Opfindelsen er yderligere illustreret ved følgende mellemprodukter og eksempler. Tyndtlagskromatografi (TLC) blev udført 20 på silica og flash-søjlekromatografi (FCC) på silica (Merck 9385). Anvendt til kromatografi betegner Solvent system A dichl orme than: ethanol:0,88 ammoniakopløsning. Organiske ekstrakter blev, hvor dét er angivet, tørret over magnesiumsulfat eller natri-25 umsulfat. Følgende forkortelser anvendes: DMF - dimethylformamid; THF - tetrahydrofuran; DME - dimethoxyethan. 1H-NMR spektre blev optaget ved 250 MHz for fortyndede opløsninger i d6-dimethylsulphoxid. Chloridformen af Amberlite harpiks IRA 400 var fra B.D.H.The invention is further illustrated by the following intermediates and examples. Thin layer chromatography (TLC) was performed on silica and flash column chromatography (FCC) on silica (Merck 9385). Used for chromatography, Solvent System A represents dichloromethane: ethanol: 0.88 ammonia solution. Organic extracts, where indicated, were dried over magnesium sulfate or sodium sulfate. The following abbreviations are used: DMF - dimethylformamide; THF - tetrahydrofuran; DME - dimethoxyethane. 1 H NMR spectra were recorded at 250 MHz for dilute solutions in d6-dimethyl sulfoxide. The chloride form of the Amberlite resin IRA 400 was from B.D.H.

Mellemprodukt 1 18 DK 169922 B1 4-[(2-Fluorphenyl)amino]-5,6-dihydro-2(IH)-pyridinonIntermediate 1 18 - [(2-Fluorophenyl) amino] -5,6-dihydro-2 (1H) -pyridinone

En blanding af 2-fluoranilin (0,98 g) og 2,4-dioxopiperidin (1,0 g) blev opvarmet ved 120°C i 2 timer. Den afkølede 5 blanding blev tritureret med tør ether (5 x 40 ml), og opløsningsmidlet blev dekanteret, hvilket gav titelforbindelsen (1,495 g), smeltepunkt 98-100°C.A mixture of 2-fluoroaniline (0.98 g) and 2,4-dioxopiperidine (1.0 g) was heated at 120 ° C for 2 hours. The cooled mixture was triturated with dry ether (5 x 40 ml) and the solvent was decanted to give the title compound (1.495 g), mp 98-100 ° C.

Mellemprodukt 3 5,6-Dihydro-4-[(2-methylphenyl)amino]-2(IH)-pyridinon 10 En blanding af o-toluidin (943 g) og 2,4-dioxopiperidin (1,0 g) blev opvarmet ved 120°C i 30 minutter. Olien blev afkølet, tritureret med ether (30 ml) , og opløsningsmidlet blev dekanteret, hvilket gav titelforbindelsen (1,74 g), smeltepunkt 155-158°C.Intermediate 3 5,6-Dihydro-4 - [(2-methylphenyl) amino] -2 (1H) -pyridinone A mixture of o-toluidine (943 g) and 2,4-dioxopiperidine (1.0 g) was heated. at 120 ° C for 30 minutes. The oil was cooled, triturated with ether (30 mL) and the solvent was decanted to give the title compound (1.74 g), mp 155-158 ° C.

15 Mellemprodukt 4 4-[(2,6-Dibromphenyl)amino]-5,6-dihydro-2(IH)-pyridinonIntermediate 4 4 - [(2,6-Dibromophenyl) amino] -5,6-dihydro-2 (1H) -pyridinone

En blanding af 2,6-dibromanilin (4,4 g) og 2,4-dioxopiperidin (2,0 g) blev opvarmet ved 120°C i 2,5 time. Blandingen blev derefter afkølet (0°C) og tritureret med ether (100 ml), 20 hvilket gav et fast stof som blev oprenset ved FCC under eluering med system A (100:8:1), hvilket gav titelforbindelsen (1,8 g), smeltepunkt 240-243°C.A mixture of 2,6-dibromaniline (4.4 g) and 2,4-dioxopiperidine (2.0 g) was heated at 120 ° C for 2.5 hours. The mixture was then cooled (0 ° C) and triturated with ether (100 mL) to give a solid which was purified by FCC eluting with System A (100: 8: 1) to give the title compound (1.8 g ), mp 240-243 ° C.

Mellemprodukt 6 4-[(2,5-Difluorphenyl)amino]-5,6-dihydro-2(IH)-pyridinon 25 En blanding af 2,5-difluoranilin (6,45 g) og 2,4-dioxopiperidin (5,66 g) blev opvarmet under nitrogen i 6 timer. Reaktionsblandingen blev derpå opløst i ethanol (50 ml), adsor- 19 DK 169922 B1 beret på silica og oprenset ved FCC under eluering med system A (150:8:1), hvilket gav titelforbindelsen (2,3 g), smeltepunkt 252-255°C.Intermediate 6 4 - [(2,5-Difluorophenyl) amino] -5,6-dihydro-2 (1H) -pyridinone A mixture of 2,5-difluoroaniline (6.45 g) and 2,4-dioxopiperidine (5 , 66 g) was heated under nitrogen for 6 hours. The reaction mixture was then dissolved in ethanol (50 ml), adsorbed on silica and purified by FCC eluting with system A (150: 8: 1) to give the title compound (2.3 g), m.p. 255 ° C.

Mellemprodukt 7 5 3-[(2-Fluorphenyl) amino]-2-cyclohexen-1-on 2-Fluoranilin (10 g) og cyclohexan-1,3-dion (10 g) blev opvarmet sammen under nitrogen ved 120°C i 1 time. Den afkølede blanding blev tritureret med ether og filtreret, hvilket gav titelforbindelsen (14,8 g), smeltepunkt 116-10 118 °C.Intermediate 7 3 - [(2-Fluorophenyl) amino] -2-cyclohexen-1-one 2-Fluoraniline (10 g) and cyclohexan-1,3-dione (10 g) were heated together under nitrogen at 120 ° C for 1 hour. 1 hour. The cooled mixture was triturated with ether and filtered to give the title compound (14.8 g), m.p. 116-10 118 ° C.

Mellemprodukt 8 6-Fluor-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol-1- onIntermediate 8 6-Fluoro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one

Kupriacetat (2,71 g) blev sat til en omrørt opløsning af 4-[(2-fluorphenyl)amino]-5,6-dihydro-2(IH) -pyridinon (1,4 g) og 15 palladium(II)-acetat (280 mg) i tør DMF (28 ml) under nitrogen. Blandingen blev opvarmet ved 130°C i 1,5 time, og opløsningsmidlet blev fjernet i vakuum. Remanensen blev behandlet med varm methanol (50 ml), og suspensionen blev filtreret og vasket med varm methanol (3 x 50 ml) . De samlede filtrater 20 blev inddampet, hvilket gav en gummi (2,16 g), som blev oprenset ved FCC under eluering med system A (200:10:1), hvilket gav titelforbindelsen (490 mg), smeltepunkt 255-257°C.Cupriacetate (2.71 g) was added to a stirred solution of 4 - [(2-fluorophenyl) amino] -5,6-dihydro-2 (1H) -pyridinone (1.4 g) and palladium (II) - acetate (280 mg) in dry DMF (28 ml) under nitrogen. The mixture was heated at 130 ° C for 1.5 hours and the solvent removed in vacuo. The residue was treated with hot methanol (50 ml) and the suspension was filtered and washed with hot methanol (3 x 50 ml). The combined filtrates 20 were evaporated to give a gum (2.16 g) which was purified by FCC eluting with System A (200: 10: 1) to give the title compound (490 mg), mp 255-257 ° C .

Mellemprodukt 10 25 2,3,4,5-Tetrahydro-6-methyl-IH-pyrido[4,3-b]indol-1-onIntermediate 10 2,3,4,5-Tetrahydro-6-methyl-1H-pyrido [4,3-b] indol-1-one

Kupriacetat (2,9 g) blev sat til en omrørt opløsning af 5,6-Dihydro-4- [ (2-methylphenyl) amino] -2 (IH) -pyridinon (1,5 g) og palladium (II)-acetat (200 mg) i tør DMF (40 ml). Blandingen blev opvarmet ved 130°C i 1 time, inddampet i vakuum, og 20 DK 169922 B1 remanensen blev ekstraheret med methanol (250 ml). Opløsningen blev koncentreret i vakuum og remanensen blev oprenset ved FCC under eluering med system A (100:8:1), hvilket gav titelforbindelsen (360 mg), smeltepunkt 300-302°C.Cupriacetate (2.9 g) was added to a stirred solution of 5,6-dihydro-4- [(2-methylphenyl) amino] -2 (1H) -pyridinone (1.5g) and palladium (II) acetate (200 mg) in dry DMF (40 ml). The mixture was heated at 130 ° C for 1 hour, evaporated in vacuo and the residue was extracted with methanol (250 ml). The solution was concentrated in vacuo and the residue was purified by FCC eluting with system A (100: 8: 1) to give the title compound (360 mg), mp 300-302 ° C.

5 Mellemprodukt 11 6-Brom-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol-l-on 4-[(2,6-Dibromphenyl)amino]-5,6-dihydro-2(IH)-pyridinon (0,5 g) blev cykliseret ifølge metoden beskrevet under mellemprodukt 10, hvilket gav titelforbindelsen (250 mg), smeltepunkt 10 268-270°C.Intermediate 11 6-Bromo-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one 4 - [(2,6-Dibromophenyl) amino] -5,6-dihydro -2 (1H) -pyridinone (0.5 g) was cyclized according to the method described under intermediate 10 to give the title compound (250 mg), mp 10 268-270 ° C.

Mellemprodukt 13 6,9-Difluor-2,3,4,5 -tetrahydro-lH-pyrido[4,3-b]indol-1-on 4-[(2,5-Difluorphenyl)amino]-5,6-dihydro-2(IH)-pyridinon (2,24 g) blev cykliseret ifølge metoden beskrevet under 15 mellemprodukt 8, hvilket gav titelforbindelsen (900 mg), smeltepunkt 221-223°C.Intermediate 13 6,9-Difluoro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one 4 - [(2,5-Difluorophenyl) amino] -5,6- dihydro-2 (1H) -pyridinone (2.24 g) was cyclized according to the method described under intermediate 8 to give the title compound (900 mg), mp 221-223 ° C.

Mellemprodukt 14 8-Fluor-1,2,3,9-tetrahydro-4H-carbazol-4-on 3-[(2-Fluorphenyl)amino]-2-cyclohexen-l-on (14,8 g), palla-20 dium (II) acetat (1 g) og kobber(II)acetat (29,5 g) blev opvarmet sammen i DMF (100 ml) under nitrogen ved 140°C i 2 timer. Opløsningsmidlet blev fjernet i vakuum, og remanensen blev oprenset ved FCC under eluering med ether, hvilket gav titelforbindelsen (10,1 g), smeltepunkt 222-224°C.Intermediate 14 8-Fluoro-1,2,3,9-tetrahydro-4H-carbazol-4-one 3 - [(2-Fluorophenyl) amino] -2-cyclohexen-1-one (14.8 g) 20 dium (II) acetate (1 g) and copper (II) acetate (29.5 g) were heated together in DMF (100 ml) under nitrogen at 140 ° C for 2 hours. The solvent was removed in vacuo and the residue was purified by FCC eluting with ether to give the title compound (10.1 g), mp 222-224 ° C.

Mellemprodukt 16 21 DK 169922 B1 2.3.4.5- Tetrahydro-6-(phenylmethoxy)-lH-pyrido[4,3-b]indol-l-onIntermediate 16 21.4 16.522 Tetrahydro-6- (phenylmethoxy) -1H-pyrido [4,3-b] indol-1-one

En blanding af 2-(phenylmethoxy)anilin (7,6 g) og 2,4-dioxo-5 piperidin (4,5 g) blev opvarmet ved 120°C under nitrogen i 3 timer. Blandingen blev derefter afkølet og oprenset ved FCC under eluering med system A (100:8:1), hvilket gav et fast stof (5,4 g). Det faste stof blev behandlet ifølge den metode, der er beskrevet under mellemprodukt 10, hvilket gav 10 titelforbindelsen (4,0 g), smeltepunkt 182-185°C.A mixture of 2- (phenylmethoxy) aniline (7.6 g) and 2,4-dioxopiperidine (4.5 g) was heated at 120 ° C under nitrogen for 3 hours. The mixture was then cooled and purified by FCC eluting with System A (100: 8: 1) to give a solid (5.4 g). The solid was treated according to the method described under intermediate 10 to give the title compound (4.0 g), mp 182-185 ° C.

Mellemprodukt 17 6 -Fluor-2,3,4,5-1etrahydro-5-methyl-lH-pyrido[4,3-b]indol-1- onIntermediate 17 6 -Fluoro-2,3,4,5-1etrahydro-5-methyl-1H-pyrido [4,3-b] indol-1-one

Natriumhydrid (60% dispersion i olie; 196 mg) blev sat til en 15 omrørt suspension af 6-fluor-2,3,4,5-tetrahydro-lH-pyri- do[4,3-b]indol-l-on (500 mg) i tør DMF (10 ml) under nitrogen. Efter 30 minutter blev opløsningen afkølet (0°C), og methyliodid (0,153 ml) blev tilsat. Efter omrøring i 15 minutter blev suspensionen hældt i vand (50 ml) og ekstra-20 heret med dichlormethan (3 x 25 ml). De samlede, tørrede, organiske ekstrakter blev inddampet, hvilket gav et fast stof (ca. 530 mg), som blev oprenset ved FCC under eluering med system A (250:10:1), hvilket gav titelforbindelsen (130 mg), smeltepunkt 242°C.Sodium hydride (60% dispersion in oil; 196 mg) was added to a stirred suspension of 6-fluoro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one (500 mg) in dry DMF (10 ml) under nitrogen. After 30 minutes, the solution was cooled (0 ° C) and methyl iodide (0.153 ml) was added. After stirring for 15 minutes, the suspension was poured into water (50 ml) and extracted with dichloromethane (3 x 25 ml). The combined dried organic extracts were evaporated to give a solid (about 530 mg) which was purified by FCC eluting with System A (250: 10: 1) to give the title compound (130 mg), m.p. ° C.

25 Mellemprodukt 19 2.3.4.5- Tetrahydro-5,6-dimethyl-lH-pyrido[4,3-b]indol-1-onIntermediate 19 2.3.4.5- Tetrahydro-5,6-dimethyl-1H-pyrido [4,3-b] indol-1-one

Natriumhydrid (60% dispersion i olie; 196 mg) blev sat til en omrørt opløsning af 2,3,4,5-tetrahydro-6-methyl-lH-pyrido-[4,3-b]indol-l-on (350 mg) i tør DMF (20 ml) ved 21°C under 30 nitrogen. Efter 15 minutter blev opløsningen afkølet (0°C) og 22 DK 169922 B1 en 10% (v/v) opløsning af methyliodid i DMF (1,6 ml) blev dråbevis tilsat. Efter 10 minutter, blev vand (150 ml) tilsat, og blandingen blev ekstraheret med ethylacetat (3 x 50 ml) . De samlede, organiske ekstrakter blev vasket med vand 5 (3 x 50 ml), derefter med saltvand (100 ml) og inddampet, hvilket gav et fast stof, som blev oprenset ved FCC under eluering med dichlormethan:methanol (80:1), hvilket gav titelforbindelsen (190 mg), smeltepunkt 298-300°C.Sodium hydride (60% dispersion in oil; 196 mg) was added to a stirred solution of 2,3,4,5-tetrahydro-6-methyl-1H-pyrido- [4,3-b] indol-1-one (350 mg) in dry DMF (20 ml) at 21 ° C under 30 nitrogen. After 15 minutes, the solution was cooled (0 ° C) and a 10% (v / v) solution of methyl iodide in DMF (1.6 ml) was added dropwise. After 10 minutes, water (150 ml) was added and the mixture was extracted with ethyl acetate (3 x 50 ml). The combined organic extracts were washed with water 5 (3 x 50 ml), then brine (100 ml) and evaporated to give a solid which was purified by FCC eluting with dichloromethane: methanol (80: 1), to give the title compound (190 mg), mp 298-300 ° C.

Mellemprodukterne 20 og 22 blev fremstillet på tilsvarende 10 måde som mellemprodukt 19, dvs. ved methylering af den relevante 2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol-l-on under anvendelse af natriumhydrid og methyliodid i DMF.The intermediates 20 and 22 were prepared in a similar manner to intermediate 19, i. by methylation of the appropriate 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one using sodium hydride and methyl iodide in DMF.

Mellemprodukt 20 6-Brom-2,3,4,5-tetrahydro-5-methyl-lH-pyrido[4,3-b]indol-l-on 15 Methylering af 6-brom-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol-l-on (200 mg) gav titelforbindelsen (80 mg), smeltepunkt 212-214°C.Intermediate 20 6-Bromo-2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indol-1-one Methylation of 6-bromo-2,3,4,5- tetrahydro-1H-pyrido [4,3-b] indol-1-one (200 mg) gave the title compound (80 mg), mp 212-214 ° C.

Mellemprodukt 22 6,9-Difluor-2,3,4,5-tetrahydro-5-methyl-lH-pyrido[4,3-b]in-20 dol-l-onIntermediate 22 6,9-Difluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indole-1-one

Methylering af 6,9-difluor-2,3,4,5-tetrahydro-lH-pyrido[4,3-b] indol-l-on (900 mg) gav titelforbindelsen (110 mg), smeltepunkt 226-229°C. (FCC-eluent var system A (150:8:1)).Methylation of 6,9-difluoro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one (900 mg) gave the title compound (110 mg), m.p. 226-229 ° C . (FCC eluent was system A (150: 8: 1)).

Mellemprodukt 24 25 8-Fluor-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-onIntermediate 24 8-Fluoro-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one

Til en suspension af natriumhydrid (80% dispersion i olie; 1,15 g) i tør DMF (50 ml) under nitrogen blev sat til 8- 23 DK 169922 B1 fluor-l,2,3,9-tetrahydro-4H-carbazol-4-on (6,5 g) i tør THF (50 ml), og blandingen blev omrørt i 1 time. Methyliodid (4,1 ml) blev tilsat, og blandingen blev omrørt i 3 timer. Blandingen blev derefter hældt i saltvand (300 ml) og ekstra-5 heret med ether (2 x 300 ml) . De samlede, tørrede, organiske ekstrakter blev inddampet i vakuum, hvilket gav titelforbindelsen (5,77 g), smeltepunkt 126-128°C.To a suspension of sodium hydride (80% dispersion in oil; 1.15 g) in dry DMF (50 ml) under nitrogen was added 8- 8- fluor-1,2,3,9-tetrahydro-4H-carbazole -4-one (6.5 g) in dry THF (50 ml) and the mixture was stirred for 1 hour. Methyl iodide (4.1 ml) was added and the mixture was stirred for 3 hours. The mixture was then poured into brine (300 ml) and extracted with ether (2 x 300 ml). The combined dried organic extracts were evaporated in vacuo to give the title compound (5.77 g), mp 126-128 ° C.

Mellemprodukt 25 2.3.4.5- Tetrahydro-5-methyl-6-(phenylmethoxy)-lH-pyrido[4,3-10 b]indol-l-on 2.3.4.5- Tetrahydro-6- (phenylmethoxy) - lH-pyrido[4,3-b] indol-1-on (2,0 g) blev methyleret ifølge metoden beskrevet under mellemprodukt 17, hvilket gav titelforbindelsen (950 mg), smeltepunkt 199-201°C. (FCC-eluent var system A (100:8:1)).Intermediate 2.3.4.5- Tetrahydro-5-methyl-6- (phenylmethoxy) -1H-pyrido [4,3-10 b] indol-1-one 2.3.4.5- Tetrahydro-6- (phenylmethoxy) -1H-pyrido [ 4,3-b] indol-1-one (2.0 g) was methylated according to the method described under Intermediate 17 to give the title compound (950 mg), mp 199-201 ° C. (FCC eluent was system A (100: 8: 1)).

15 Mellemprodukt 26 6-Fluor-2,3,4,5-tetrahydro-5-[(phenylmethoxy)methyl]-1H-pyrido[4,3-b]indol-l-on 6-Fluor-2,3,4,5-tetrahydro-lH-pyrido[4,3-b]indol-l-on (800 mg) blev alkyleret med benzylchlormethylether (0,55 ml) 20 ifølge metoden beskrevet under mellemprodukt 17, hvilket gav titelforbindelsen (220 mg), smeltepunkt 130-132°C. (FCC-eluent var system A (300:10:1)).Intermediate 26 6-Fluoro-2,3,4,5-tetrahydro-5 - [(phenylmethoxy) methyl] -1H-pyrido [4,3-b] indol-1-one 6-Fluoro-2,3,4 5-Tetrahydro-1H-pyrido [4,3-b] indol-1-one (800 mg) was alkylated with benzyl chloromethyl ether (0.55 ml) according to the method described under Intermediate 17 to give the title compound (220 mg), mp 130-132 ° C. (FCC eluent was system A (300: 10: 1)).

Mellemprodukt 27 2.3.4.5- Tetrahydro-6- (phenylmethoxy) -5- [ (phenylmethoxy) me-25 thyl]-lH-pyrido[4,3-b]indol-l-on 2,3,4,5 -Tetrahydro- 6- (phenylmethoxy) - IH-pyrido [4,3 -b] indol -1-on (1,8 g) blev alkyleret med benzylchlormethylether (0,86 ml) ifølge metoden beskrevet under mellemprodukt 19, hvilket 24 DK 169922 B1 gav titelforbindelsen (600 mg), smeltepunkt 188-190°C. (FCC-eluent var system A (100:8:1)).Intermediate 27 2.3.4.5- Tetrahydro-6- (phenylmethoxy) -5- [(phenylmethoxy) methyl] -1H-pyrido [4,3-b] indol-1-one 2,3,4,5-Tetrahydro 6- (Phenylmethoxy) - 1H-pyrido [4,3-b] indol-1-one (1.8 g) was alkylated with benzyl chloromethyl ether (0.86 ml) according to the method described under Intermediate 19, which 24 afforded the title compound (600 mg), mp 188-190 ° C. (FCC eluent was system A (100: 8: 1)).

Mellemprodukt 28 6-Fluor-2,3,4,5-tetrahydro-5-(1-methylethyl)-lH-pyrido[4,3-5 b]indol-l-onIntermediate 28 6-Fluoro-2,3,4,5-tetrahydro-5- (1-methylethyl) -1H-pyrido [4,3-5 b] indol-1-one

En omrørt opløsning af 6-fluor-2,3,4,5-tetrahydro-lH-pyrido-[4,3-b]indol-l-on (1,006 g) i tør DMF (50 ml) blev behandlet med natriumhydrid (73,2% dispersion i olie; 333 mg) og omrørt under nitrogen i 1 time. Isopropylbromid (663 mg) blev der-10 efter tilsat, og opløsningen blev omrørt ved stuetemperatur i 30 minutter og derefter ved 50°C i 12 timer. En yderligere mængde isopropylbromid (150 mg) blev derefter tilsat, og blandingen blev derefter omrørt under nitrogen ved 50°C i ca. 60 timer. Blandingen blev derefter afkølet til stuetemperatur 15 og sat til vand (300 ml). Blandingen blev derefter ekstraheret med dichlormethan (3 x 200 ml), adsorberet på silica og oprenset ved FCC under eluering med system A (150:8:1), hvilket gav et fast stof (240 mg), som blev tritureret med ether, hvilket gav titelforbindelsen (130 mg), smeltepunkt 20 183-184°C.A stirred solution of 6-fluoro-2,3,4,5-tetrahydro-1H-pyrido- [4,3-b] indol-1-one (1.006 g) in dry DMF (50 ml) was treated with sodium hydride ( 73.2% dispersion in oil; 333 mg) and stirred under nitrogen for 1 hour. Isopropyl bromide (663 mg) was then added and the solution was stirred at room temperature for 30 minutes and then at 50 ° C for 12 hours. An additional amount of isopropyl bromide (150 mg) was then added and the mixture was then stirred under nitrogen at 50 ° C for approx. 60 hours. The mixture was then cooled to room temperature and added to water (300 ml). The mixture was then extracted with dichloromethane (3 x 200 ml), adsorbed on silica and purified by FCC eluting with System A (150: 8: 1) to give a solid (240 mg) which was triturated with ether, gave the title compound (130 mg), m.p. 183-184 ° C.

Mellemprodukt 29 5-(Cyclopentylmethyl)-6-fluor-2,3,4,5-tetrahydro-lH-pyri-do[4,3-b]indol-l-onIntermediate 29 5- (Cyclopentylmethyl) -6-fluoro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one

En omrørt opløsning af 6-fluor-2,3,4,5-tetrahydro-lH-pyri-25 do[4,3-b] indol-l-on (1,023 g) i tør DMF (50 ml) blev behandlet med natriumhydrid (73,2% dispersion i olie; 331 mg) og omrørt under nitrogen ved stuetemperatur i 30 minutter. En opløsning af cyclopentylmethyl(methylsulfonat) (893 mg) i tør DMF (20 ml) blev derefter tilsat i løbet af 15 minutter, og 30 omrøring fortsattes i 5 dage. Vand (20 ml) blev sat til reaktionsblandingen, som derefter blev koncentreret i vakuum, hvilket gav et fast stof. Dette blev opløst i ethylacetat 25 DK 169922 B1 (300 ml) og methanol (1 ml), og den resulterende opløsning blev vasket med mættet natriumchloridopløsning (3 x 100 ml) og derefter adsorberet på silica. Oprensning ved FCC under eluering med system A (150:8:1) gav et fast stof (283 mg), 5 som blev omkrystalliseret fra ethylacetat, hvilket gav titel-forbindelsen (237 mg), smeltepunkt 175-176°C.A stirred solution of 6-fluoro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indol-1-one (1.023 g) in dry DMF (50 ml) was treated with sodium hydride (73.2% dispersion in oil; 331 mg) and stirred under nitrogen at room temperature for 30 minutes. A solution of cyclopentylmethyl (methylsulfonate) (893 mg) in dry DMF (20 ml) was then added over 15 minutes and stirring was continued for 5 days. Water (20 ml) was added to the reaction mixture which was then concentrated in vacuo to give a solid. This was dissolved in ethyl acetate (300 ml) and methanol (1 ml) and the resulting solution was washed with saturated sodium chloride solution (3 x 100 ml) and then adsorbed on silica. Purification by FCC eluting with system A (150: 8: 1) gave a solid (283 mg), which was recrystallized from ethyl acetate to give the title compound (237 mg), mp 175-176 ° C.

Mellemprodukt 30 8 -Fluor-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4 -on-oximIntermediate 8-Fluoro-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one oxime

En blanding af 8-fluor-l,2,3,9-tetrahydro-9-methyl-4H-carba-10 zol-4-on (3,0 g) og hydroxylaminhydrochlorid (2,92 g) i pyridin (ca. 35 ml) blev opvarmet ved 60°C i 3 timer. Opløsningen blev koncentreret i vakuum, derefter tørret azeo-tropt med toluen (2 x 10 ml) . Remanensen blev behandlet med 8% natriumhydrogencarbonatopløsning (125 ml) og ekstraheret 15 med ethylacetat (3 x 100 ml). De samlede ekstrakter blev filtreret og koncentreret i vakuum, hvilket gav titelforbindelsen (1,8 g) som et fast stof, TLC (system A, 100:8:1), Rf 0,66.A mixture of 8-fluoro-1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one (3.0 g) and hydroxylamine hydrochloride (2.92 g) in pyridine (ca. 35 ml) was heated at 60 ° C for 3 hours. The solution was concentrated in vacuo, then dried azeotroped with toluene (2 x 10 ml). The residue was treated with 8% sodium bicarbonate solution (125 ml) and extracted with ethyl acetate (3 x 100 ml). The combined extracts were filtered and concentrated in vacuo to give the title compound (1.8 g) as a solid, TLC (system A, 100: 8: 1), Rf 0.66.

Mellemprodukt 31 20 7-Fluor-3,4,5,6-tetrahydro-6-methylazepino[4,3-b]indol-1(2H)- onIntermediate 31 7-Fluoro-3,4,5,6-tetrahydro-6-methyllazepino [4,3-b] indol-1 (2H) -one

En blanding af 8-fluor-1,2,3,9-tetrahydro-9-methyl-4H-carbazol -4 -on -oxim (1,8 g) og polyphosphorsyre (ca 20 ml) i dioxan (30 ml) blev omrørt under nitrogen ved 100-110°C i 1 time.A mixture of 8-fluoro-1,2,3,9-tetrahydro-9-methyl-4H-carbazole-4-one oxime (1.8 g) and polyphosphoric acid (about 20 ml) in dioxane (30 ml) was stirred under nitrogen at 100-110 ° C for 1 hour.

25 Efter afkøling blev reaktionsblandingen hældt i isvand (1 1), og den resulterende suspension blev ekstraheret med dichlor-methan. Det organiske ekstrakt blev koncentreret i vakuum, hvilket gav et fast stof, som blev taget op i methanol og adsorberet på silica. Oprensning ved FCC under eluering med 30 system A (200:8:1) gav titelforbindelsen (850 mg), smeltepunkt 233-235°C.After cooling, the reaction mixture was poured into ice water (1 L) and the resulting suspension was extracted with dichloromethane. The organic extract was concentrated in vacuo to give a solid which was taken up in methanol and adsorbed on silica. Purification by FCC eluting with System A (200: 8: 1) afforded the title compound (850 mg), mp 233-235 ° C.

Mellemprodukt 32 26 DK 169922 B1 2,3,4,5-Tetrahydro-5-methyl-1-oxo-IH-pyrido[4,3-b]indol-6-carbonitrilIntermediate 32 2,3,4,5-Tetrahydro-5-methyl-1-oxo-1H-pyrido [4,3-b] indole-6-carbonitrile

En blanding af 6-brom-2,3,4,5-tetrahydro-5-methyl-lH-pyri-5 do[4,3-b] indol-l-on (1,1 g) og kuprocyanid (1,0 g) i 1,3-dimethyl-3,4,5,6-tetrahydro-2(IH)-pyrimidon (30 ml) blev opvarmet ved 180°C i 24 timer. Blandingen blev hældt på is (ca. 500 ml) og ferri(III) chlorid (20 g) og omrørt i 1 time.A mixture of 6-bromo-2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indol-1-one (1.1 g) and cuprocyanide (1, 0 g) in 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidone (30 ml) was heated at 180 ° C for 24 hours. The mixture was poured onto ice (about 500 ml) and ferric (III) chloride (20 g) and stirred for 1 hour.

Den blev derefter ekstraheret med dichlormethan (3 x 300 ml), 10 og de samlede organiske ekstrakter blev vasket med vand (2 x 300 ml) og koncentreret i vakuum. Remanensen blev tritureret med hexan (250 ml) efterfulgt af en ether/hexan-blanding (50:50; 100 ml) og til slut med ether (60 ml), hvilket gav titelforbindelsen (620 mg), smeltepunkt 230-231°C.It was then extracted with dichloromethane (3 x 300 ml), 10 and the combined organic extracts were washed with water (2 x 300 ml) and concentrated in vacuo. The residue was triturated with hexane (250 ml) followed by an ether / hexane mixture (50:50; 100 ml) and finally with ether (60 ml) to give the title compound (620 mg), mp 230-231 ° C.

15 Mellemprodukt 34 6-Fluor-2,5 -dihydro-5-methyl-IH-pyrido[4,3-b]indol-1-onIntermediate 34 6-Fluoro-2,5-dihydro-5-methyl-1H-pyrido [4,3-b] indol-1-one

En blanding af 6-fluor-2,3,4,5-tetrahydro-5-methyl-lH-pyri-do[4,3-b]indol-l-on (300 mg) og 10% palladiumoxid-på-trækul (50% vandig pasta; 150 mg) som katalysator i ethylenglycol 20 (30 ml) blev opvarmet ved tilbagesvaling under nitrogen i 24 timer. Den afkølede blanding blev filtreret og inddampet, hvilket gav et fast stof (ca. 300 mg), som blev oprenset ved FCC under eluering med system A (200:10:1), hvilket gav et fast stof (100 mg). En prøve af dette faste stof blev yderli-25 gere oprenset ved HPLC på en Spherisorb 55W kolonne, under eluering med system A (95:5:0,5) med en hastighed på 15 ml/minut, hvilket gav titelforbindelsen, smeltepunkt 294-296°C.A mixture of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indol-1-one (300 mg) and 10% palladium oxide-on-charcoal (50% aqueous paste; 150 mg) as catalyst in ethylene glycol 20 (30 ml) was heated at reflux under nitrogen for 24 hours. The cooled mixture was filtered and evaporated to give a solid (about 300 mg) which was purified by FCC eluting with System A (200: 10: 1) to give a solid (100 mg). A sample of this solid was further purified by HPLC on a Spherisorb 55W column, eluting with system A (95: 5: 0.5) at a rate of 15 ml / minute to give the title compound, m.p. 296 ° C.

mm

Mellemprodukt 35 27 DK 169922 B1 6-Fluor-2,3,4,5-tetrahydro-2-[(5-methyl-lH-imidazol-4-yl)-methyl]-5-[(phenylmethoxy)methyl]-lH-pyrido[4,3-b]indol-l-onIntermediate 35-Fluoro-2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) -methyl] -5 - [(phenylmethoxy) methyl] -1H -pyrido [4,3-b] indol-l-one

Natriumhydrid (60% dispersion i olie; 28 mg) blev sat til en 5 omrørt suspension af 6-fluor-2,3,4,5-tetrahydro-5-[(phenyl-methoxy)methyl]-lH-pyrido[4,3-b]indol-l-on (190 mg) i tør DME (10 ml). Blandingen blev opvarmet ved 50°C i 6 timer, derefter behandlet med 4-(chlormethyl)-5-methyl-l-(triphenylme-thyl)-lH-imidazol (261 mg), og omrøring fortsattes under 10 nitrogen i 18 timer. Vand (2 ml) og eddikesyre (2 ml) blev tilsat, og opløsningen blev opvarmet ved tilbagesvaling i 2,5 time. Opløsningen blev hældt i en 8% natriumhydrogencarbonat-opløsning (50 ml) og ekstraheret med dichlormethan (3 x 25 ml). De samlede, tørrede, organiske ekstrakter blev inddam-15 pet, hvilket gav en olie (ca. 750 mg), som blev oprenset ved FCC under eluering med system A (200:10:1), hvilket gav titelforbindelsen (188 mg), TLC (system A, 200:10:1), Rf 0,33.Sodium hydride (60% dispersion in oil; 28 mg) was added to a 5 stirred suspension of 6-fluoro-2,3,4,5-tetrahydro-5 - [(phenylmethoxy) methyl] -1H-pyrido [4 3-b] indol-1-one (190 mg) in dry DME (10 ml). The mixture was heated at 50 ° C for 6 hours, then treated with 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (261 mg) and stirring was continued under 10 nitrogen for 18 hours. Water (2 ml) and acetic acid (2 ml) were added and the solution was heated at reflux for 2.5 hours. The solution was poured into an 8% sodium bicarbonate solution (50 ml) and extracted with dichloromethane (3 x 25 ml). The combined dried organic extracts were evaporated to give an oil (about 750 mg) which was purified by FCC eluting with System A (200: 10: 1) to give the title compound (188 mg). TLC (system A, 200: 10: 1), Rf 0.33.

Mellemprodukt 36 20 6-Fluor-2,3,4,5-tetrahydro-2-[(5-methyl-1-(triphenylmethyl)-lH-imidazol-4-yl)methyl]-lH-pyrido[4,3-b]indol-l-onIntermediate 36 6-Fluoro-2,3,4,5-tetrahydro-2 - [(5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl) methyl] -1H-pyrido [4,3- b] indol-l-one

En opløsning af triphenylmethylchlorid (0,625 g) i tør DMF (10 ml) blev dråbevis sat til en omrørt opløsning af 6-fluor- 2,3,4,5-tetrahydro-2-[(5-methyl-IH-imidazol-4-yl)methyl]-1H-25 pyrido[4,3-b]indol-l-on (530 mg) i tør DMF (20 ml) indeholdende triethylamin (0,25 g). Reaktionsblandingen blev derefter omrørt ved stuetemperatur i 20 timer, sat til vand (500 ml) og ekstraheret med ethylacetat (3 x 200 ml). De samlede organiske ekstrakter blev vasket med vand (2 x 300 ml), 30 tørret og adsorberet på silica. Oprensning ved FCC under eluering med system A (150:8:1) gav titelforbindelsen (509 mg), smeltepunkt 252-253°C.A solution of triphenylmethyl chloride (0.625g) in dry DMF (10ml) was added dropwise to a stirred solution of 6-fluoro-2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazole-4) -yl) methyl] -1H-pyrido [4,3-b] indol-1-one (530 mg) in dry DMF (20 ml) containing triethylamine (0.25 g). The reaction mixture was then stirred at room temperature for 20 hours, added to water (500 ml) and extracted with ethyl acetate (3 x 200 ml). The combined organic extracts were washed with water (2 x 300 ml), dried and adsorbed on silica. Purification by FCC eluting with system A (150: 8: 1) afforded the title compound (509 mg), mp 252-253 ° C.

Mellemprodukt 37 28 DK 169922 B1 2,3,4,5-Tetrahydro-2 -[(5-methyl-iH-imidazol-4-yl)methyl]-6-(phenylmethoxy)-5-[(phenylmethoxy)methyl]-lH-pyrido[4,3-b]indol-l-on 5 2,3,4,5-Tetrahydro-6-(phenylmethoxy)-5-[(phenylmethoxy)me- thyl]-lH-pyrido[4,3-b]indol-l-on (500 g) blev omsat med 4-(chlormethyl)-5-methyl-l-(triphenylmethyl)-lH-imidazol (671 mg) ifølge metoden beskrevet under mellemprodukt 35, hvilket gav titelforbindelsen (340 mg), smeltepunkt 170-172°C. (FCC-10 eluent var system A (100:8:1)).Intermediate 37 2,3,4,5-Tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -6- (phenylmethoxy) -5 - [(phenylmethoxy) methyl] - 1H-pyrido [4,3-b] indol-1-one 2,3,4,5-Tetrahydro-6- (phenylmethoxy) -5 - [(phenylmethoxy) methyl] -1H-pyrido [4.3 -b] indol-1-one (500 g) was reacted with 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (671 mg) according to the method described under intermediate 35 to give the title compound (340 mg), mp 170-172 ° C. (FCC-10 eluent was system A (100: 8: 1)).

Mellemprodukt 38 4-[(6-Brom-2,3,4,5-tetrahydro-5-methyl-1-oxo-lH-pyrido[4,3- b]indol-2-yl)methyl]-N, N, 5-1rime thyl-IH-imidazol-1-sulfonamidIntermediate 38 4 - [(6-Bromo-2,3,4,5-tetrahydro-5-methyl-1-oxo-1H-pyrido [4,3-b] indol-2-yl) methyl] -N, N , 5-1 trimethyl-1H-imidazole-1-sulfonamide

Dimethylsulfamoylchlorid (0,31 ml) blev dråbevis sat til en 15 omrørt suspension af 6-brom-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-lH-imidazol-4-yl)methyl]-lH-pyrido[4,3-b]indol-l-on (1,1 g) og triethylamin (0,48 ml) i tør dichlormethan (100 ml). Blandingen blev opvarmet ved tilbagesvaling i 18 timer, hvorefter en yderligere mængde triethylamin (0,48 ml) 20 og dimethylsulfamoylchlorid (0,31 ml) blev tilsat. Opløsningen blev opvarmet ved tilbagesvaling i 8 timer og henstod ved 2l°C i ca. 60 timer. Opløsningen blev koncentreret i vakuum og oprenset ved FCC under eluering med system A (100:8:1), hvilket gav et fast stof, som blev tritureret med hexan 25 (50 ml), hvilket gav titelforbindelsen (500 mg), smeltepunkt 182-185°C.Dimethylsulfamoyl chloride (0.31ml) was added dropwise to a stirred suspension of 6-bromo-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indol-1-one (1.1 g) and triethylamine (0.48 ml) in dry dichloromethane (100 ml). The mixture was heated at reflux for 18 hours, after which an additional amount of triethylamine (0.48 ml) 20 and dimethylsulfamoyl chloride (0.31 ml) were added. The solution was heated at reflux for 8 hours and allowed to stand at 21 ° C for approx. 60 hours. The solution was concentrated in vacuo and purified by FCC eluting with system A (100: 8: 1) to give a solid which was triturated with hexane (50 mL) to give the title compound (500 mg), m.p. 185 ° C.

6-Fluor-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-IH-imidazol- 4-yl)methyl]-lH-pyrido[4,3-b]indol-l-on-maleat EKSEMPEL 1 29 DK 169922 B16-Fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indole-1 -on-maleate EXAMPLE 1 29 DK 169922 B1

Natriumhydrid (60% dispersion i olie; 25 mg) blev sat til en 5 omrørt suspension af 6-fluor-2,3,4,5-tetrahydro-5-methyl-lH-pyrido[4,3-b] indol-l-on (115 mg) i tør DME (7,5 ml) under nitrogen. Blandingen blev opvarmet ved 50°C i 6 timer, derefter behandlet med 4-(chlormethyl)-5-methyl-l-(triphenylme-thyl)-IH-imidazol (236 mg), og omrøring fortsattes ved 50°C i 10 18 timer. Vand (1,25 ml) og eddikesyre (1,25 ml) blev tilsat, og opløsningen blev opvarmet ved tilbagesvaling i 6 timer. Opløsningen blev hældt i 8% natriumhydrogencarbonatopløsning (40 ml) og ekstraheret med dichlormethan (3 x 20 ml). De samlede, tørrede, organiske ekstrakter blev inddampet, hvil-15 ket gav et fast stof (375 mg), som blev oprenset ved FCC under eluering med system A (200:10:1), hvilket gav den fri base af titelforbindelsen som et fast stof (147 mg). Dette blev opløst i dichlormethan (3 ml) og behandlet med en opløsning af maleinsyre (55 mg) i absolut ethanol (0,5 ml).Sodium hydride (60% dispersion in oil; 25 mg) was added to a 5 stirred suspension of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indole-1 -one (115 mg) in dry DME (7.5 ml) under nitrogen. The mixture was heated at 50 ° C for 6 hours, then treated with 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (236 mg) and stirring was continued at 50 ° C for 18 hours. hours. Water (1.25 ml) and acetic acid (1.25 ml) were added and the solution was heated at reflux for 6 hours. The solution was poured into 8% sodium bicarbonate solution (40 ml) and extracted with dichloromethane (3 x 20 ml). The combined dried organic extracts were evaporated to give a solid (375 mg) which was purified by FCC eluting with System A (200: 10: 1) to give the free base of the title compound as solid (147 mg). This was dissolved in dichloromethane (3 ml) and treated with a solution of maleic acid (55 mg) in absolute ethanol (0.5 ml).

20 Opløsningsmidlet blev fjernet i vakuum, og remanensen blev tritureret med tør ether (3 x 5 ml), hvilket gav titelforbindelsen (185 mg), smeltepunkt 178-180°C.The solvent was removed in vacuo and the residue was triturated with dry ether (3 x 5 ml) to give the title compound (185 mg), mp 178-180 ° C.

Analyse Ci7Hi7FN40.C4H404Analysis Ci7Hi7FN40.C4H404

Fundet: C, 59,0; H, 5,0; N, 12,85; 25 Beregnet: C, 58,9; H, 4,9; N, 13,1%.Found: C, 59.0; H, 5.0; N, 12.85; Calculated: C, 58.9; H, 4.9; N, 13.1%.

Eksemplerne 3, 4, 6, 7, 9, 10, 12 og 13 blev fremstillet på en tilsvarende måde som anført i eksempel 1, dvs. ved omsætning af den relevante lactam med 4-(chlormethyl)-5-methyl-1-(triphenylmethyl)-IH-imidazol (i det følgende betegnet 30 forbindelse X) i DME i nærværelse af natriumhydrid. Afbe-skyttelse blev udført med eddikesyre og vand, og hvorefter opløsningen blev gjort basisk med 2N natriumhydroxidopløsning frem for 8% natriumhydrogencarbonatopløsning. Den basiske opløsning blev derefter ekstraheret med dichlormethan (eller 30 DK 169922 B1 i eksemplerne 6 og 12 ethylacetat), og de samlede, tørrede, organiske ekstrakter blev inddampet i vakuum. Remanensen blev oprenset ved FCC under eluering med system A [eksemplerne 3, 6, 7, 12, 13 (150:8:1) og eksemplerne 4, 9, 10 (100:8:1)3, 5 hvilket gav den fri base af titelforbindelsen. Maleatdannel-sen blev udført som beskrevet i eksempel 1 bortset fra, at methanol blev anvendt (i stedet for ethanol) som omkrystallisationsopløsningsmiddel, og blandingen blev opvarmet på dampbad i 10 minutter. Produktet blev opnået ud fra denne 10 methanoliske opløsning enten ved inddampning til tørhed i vakuum og efterfølgende triturering af den resulterende remanens med ether (eksemplerne 4 og 9) eller omkrystallisation af remanensen fra en blanding af methanol og ether (eksempel 10), eller produktet blev udfældet fra methanolop-15 løsningen ved tilsætning af ether (eksemplerne 3, 6, 7, 12, 13) .Examples 3, 4, 6, 7, 9, 10, 12 and 13 were prepared in a similar manner as set forth in Example 1, ie. by reacting the relevant lactam with 4- (chloromethyl) -5-methyl-1- (triphenylmethyl) -1H-imidazole (hereinafter referred to as compound X) in DME in the presence of sodium hydride. Deprotection was performed with acetic acid and water and then the solution was basified with 2N sodium hydroxide solution rather than 8% sodium hydrogen carbonate solution. The basic solution was then extracted with dichloromethane (or Examples 6 and 12 ethyl acetate) and the combined dried organic extracts were evaporated in vacuo. The residue was purified by FCC eluting with System A [Examples 3, 6, 7, 12, 13 (150: 8: 1) and Examples 4, 9, 10 (100: 8: 1) 3, giving the free base of the title compound. The maleate formation was carried out as described in Example 1 except that methanol was used (instead of ethanol) as recrystallization solvent and the mixture was heated on a steam bath for 10 minutes. The product was obtained from this methanolic solution either by evaporation to dryness in vacuo and subsequent trituration of the resulting residue with ether (Examples 4 and 9) or recrystallization of the residue from a mixture of methanol and ether (Example 10), or precipitated from the methanol solution by the addition of ether (Examples 3, 6, 7, 12, 13).

EKSEMPEL 3 2,3,4,5-Tetrahydro-5,6-dimethyl-2-[(5-methyl-IH-imidazol-4-yl)methyl]-IH-pyrido[4,3-b]indol-l-on-maleat 20 Omsætningen af 2,3,4,5-tetrahydro-5,6-dimethyl-IH-pyrido[4,3-b]indol-l-on (150 mg) med forbindelse X (260 mg) gav den fri base af titelforbindelsen (120 mg). Maleatdannelsen gav titelforbindelsen (110 mg), TLC (system A, 150:8:1), Rf 0,3.EXAMPLE 3 2,3,4,5-Tetrahydro-5,6-dimethyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indole-1 The reaction of 2,3,4,5-tetrahydro-5,6-dimethyl-1H-pyrido [4,3-b] indol-1-one (150 mg) with compound X (260 mg) gave the free base of the title compound (120 mg). The maleate formation gave the title compound (110 mg), TLC (system A, 150: 8: 1), Rf 0.3.

^-NMR 62,35 (3H,s), 2,75 (3H,s), 3,08 (2H,t), 3,64 (2H,t), 25 3,93 (3H,s), 4,62 (2H,s), 6,07 (2H,s), 6,90 (lH,brd), 7,01 (IH,t), 7,88 (lH,brd), 8,73 (lH,brs).1 H-NMR 62.35 (3H, s), 2.75 (3H, s), 3.08 (2H, t), 3.64 (2H, t), 3.93 (3H, s), 4 , 62 (2H, s), 6.07 (2H, s), 6.90 (1H, brd), 7.01 (1H, t), 7.88 (1H, brd), 8.73 (1H, brs).

S-Brom-2,3,4,5-tetrahydro-5-methyl-2 -[(5-methyl-IH-imidazol- 4-yl)methyl]-lH-pyrido[4,3-b]indol-l-on-maleat 31 DK 169922 B1 EKSEMPEL 4S-Bromo-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indole-1 -on-maleate 31 EXAMPLE 4 EXAMPLE 4

Omsætningen af 6-brom-2,3,4,5-tetrahydro-5-methyl-lH-pyri-5 do[4,3-b] indol-l-on (140 mg) med forbindelse X (280 mg) gav den fri base af titelforbindelsen (130 mg). Maleatdannelse gav titelforbindelsen (170 mg), smeltepunkt 155°C.The reaction of 6-bromo-2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indol-1-one (140 mg) with compound X (280 mg) gave the free base of the title compound (130 mg). Maleate formation gave the title compound (170 mg), mp 155 ° C.

Vandanalyse fundet 2,86 vægtprocent s 0,79 mol H20.Water analysis found 2.86% by weight s 0.79 mol H2 O.

Analyse C17H17BrN40.C4H404.0,79 H20 10 Fundet: C, 50,1; H, 4,4; N, 10,7;Analysis C17H17BrN40.C4H404.0.79 H2 O Found: C, 50.1; H, 4.4; N, 10.7;

Beregnet: C, 50,1; H, 4,5; N, 11,1%.Calculated: C, 50.1; H, 4.5; N, 11.1%.

EKSEMPEL 6 6,9-Difluor-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl) methyl]-lH-pyrido[4,3-b]indol-1-on-maleat 15 Omsætningen af 6,9-difluor-2,3,4,5-tetrahydro-5-methyl-lH- pyrido[4,3-b]indol-l-on (1,0 g) med forbindelse X (1,7 g) gav den fri base af titelforbindelsen (846 mg). Maleatdannelse gav titelforbindelsen (920 mg), smeltepunkt 206-208°C.Example 6 6,9-Difluoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b ] indol-1-one maleate The reaction of 6,9-difluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indol-1-one (1.0 g) with compound X (1.7 g) gave the free base of the title compound (846 mg). Maleate formation gave the title compound (920 mg), mp 206-208 ° C.

Analyse C17H16N4°-C4H4°4 20 Fundet: C, 56,1; H, 4,6; N, 12,6;Analysis C17H16N4 ° -C4H4 ° 4 Found: C, 56.1; H, 4.6; N, 12.6;

Beregnet: C, 56,5; H, 4,5; N, 12,6%.Calculated: C, 56.5; H, 4.5; N, 12.6%.

7-Fluor-3,4,5,6-tetrahydro-6-methyl-2-[(5-methyl-IH-imidazol- 4-yl)me-thyl]-azepino[4,3-b]indol-1(2H)-on-maleat 32 DK 169922 B1 EKSEMPEL 77-Fluoro-3,4,5,6-tetrahydro-6-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -azepino [4,3-b] indole-1 (2H) -one maleate Example 7

Omsætningen af 7-fluor-3,4,5,6-tetrahydro-6-methylazepi-5 no[4,3-b]indol-1(2H)-on (850 mg) med forbindelse X (1,64 g) gav den fri base af titelforbindelsen (358 mg). Maleatdannel-se gav titelforbindelsen (383 mg), smeltepunkt 143-145°C.The reaction of 7-fluoro-3,4,5,6-tetrahydro-6-methyllazepin-5,3-b] indole-1 (2H) -one (850 mg) with compound X (1.64 g) gave the free base of the title compound (358 mg). Maleate formation gave the title compound (383 mg), mp 143-145 ° C.

Vandanalyse fundet 1,19 vægtprocent s o,296 mol H20.Water analysis found 1.19% by weight s o, 296 moles of H2 O.

Analyse C18H19N4OF.C4H4O4.0,296 H20 10 Fundet: C, 59,2; H, 5,6; N, 12,5;Analysis C18H19N4OF.C4H4O4.0.296 H2 O Found: C, 59.2; H, 5.6; N, 12.5;

Beregnet: C, 59,0; H, 5,3; N, 12,5%.Calculated: C, 59.0; H, 5.3; N, 12.5%.

EKSEMPEL 9 2.3.4.5- Tetrahydro-5-methyl-2-[(5-methyl-IH-imidazol-4-yl)-methyl]-6-(phenylmethoxy)-lH-pyrido[4,3-b] indol-1-on-maleat 15 Omsætningen af 2,3,4,5-tetrahydro-5-methyl-lH-pyrido[4,3-b]indol-l-on (900 mg) med forbindelse X (1,6 g) gav den fri base af titelforbindelsen (800 mg). En del af den fri base (90 mg) blev behandlet med maleinsyre, hvilket gav titelforbindelsen (90 mg), smeltepunkt 158-160°C. TLC (system A, 20 100:8:1), Rf 0,2.EXAMPLE 9 2.3.4.5- Tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -6- (phenylmethoxy) -1H-pyrido [4,3-b] indole 1-one maleate The reaction of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indol-1-one (900 mg) with compound X (1.6 g) gave the free base of the title compound (800 mg). Part of the free base (90 mg) was treated with maleic acid to give the title compound (90 mg), mp 158-160 ° C. TLC (system A, 100: 8: 1), Rf 0.2.

EKSEMPEL 10 2.3.4.5- Tetrahydro-5-methyl-2-[(5-methyl-lH-imidazol-4-yl)-methyl]-1-oxo-lH-pyrido[4,3-b]indol-6-carbonitril-maleatExample 10 2.3.4.5- Tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) -methyl] -1-oxo-1H-pyrido [4,3-b] indole-6- carbonitrile maleate

Omsætningen af 2,3,4,5-tetrahydro-5-methyl-l-oxo-lH-pyrido-25 [4,3-b]indol-6-carbonitril (550 mg) med forbindelse X (1,3 g) gav den fri base af titelforbindelsen (410 mg). En del af den .The reaction of 2,3,4,5-tetrahydro-5-methyl-1-oxo-1H-pyrido-25 [4,3-b] indole-6-carbonitrile (550 mg) with compound X (1.3 g) gave the free base of the title compound (410 mg). Part of it.

33 DK 169922 B1 fri base (100 mg) blev behandlet med maleinsyre, hvilket gav titelforbindelsen (50 mg), TLC (system A, 100:8:1), Rf 0,2.B1 free base (100 mg) was treated with maleic acid to give the title compound (50 mg), TLC (system A, 100: 8: 1), Rf 0.2.

Analyse C18H17N50.C4H404Analysis C18H17N50.C4H404

Fundet: C, 60,4; H, 4,8; N, 15,6; 5 Beregnet: C, 60,7; H, 4,9; N, 16,0%.Found: C, 60.4; H, 4.8; N, 15.6; Calculated: C, 60.7; H, 4.9; N, 16.0%.

EKSEMPEL 12 6-Fluor-2,3,4,5-tetrahydro-5-(l-methylethyl)-2-[ (5-methyl-1H-imidazol-4-yl)methyl] -lH-pyrido [4,3-b] indol-l-on-maleatExample 12 6-Fluoro-2,3,4,5-tetrahydro-5- (1-methylethyl) -2- [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4.3 -b] indole-l-on-maleate

Omsætningen af 6-fluor-2,3,4,5-tetrahydro-5-(l-methylethyl)-10 lH-pyrido[4,3-b]indol-l-on (130 mg) med forbindelse X (295 mg) gav den fri base af titelforbindelsen (69 mg). En del af den fri base (66 mg) blev behandlet med maleinsyre, hvilket gav titelforbindelsen (79 mg), smeltepunkt 185-187°C.The reaction of 6-fluoro-2,3,4,5-tetrahydro-5- (1-methylethyl) -10H-pyrido [4,3-b] indol-1-one (130 mg) with compound X (295 mg ) gave the free base of the title compound (69 mg). Part of the free base (66 mg) was treated with maleic acid to give the title compound (79 mg), mp 185-187 ° C.

Analyse C19H21FN40.C4H404 15 Fundet: C, 60,2; H, 5,6; N, 12,0;Analysis C19H21FN40.C4H404 Found: C, 60.2; H, 5.6; N, 12.0;

Beregnet: C, 60,5; H, 5,5; N, 12,3%.Calculated: C, 60.5; H, 5.5; N, 12.3%.

EKSEMPEL 13 34 DK 169922 B1 5- (Cyclopentylmethyl)-6-fluor-2,3,4,5-tetrahydro-2-[(5-methyl -IH-imidazol-4-yl)methyl]-IH-pyrido[4,3 -b3 indol-1-on-maleat 5 Omsætningen af 5-(cyclopentylmethyl)- 6- fluor-2,3,4,5-tetrahy-dro-lH-pyrido[4,3-b]indol-l-on (222 mg) med forbindelse X (317 mg) gav den fri base af titelforbindelsen (100 mg). Maleatdannelse gav titelforbindelsen (85 mg), smeltepunkt 164-166°C.Example 13 34 5- (Cyclopentylmethyl) -6-fluoro-2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4 3-b3 indol-1-one maleate The reaction of 5- (cyclopentylmethyl) - 6-fluoro-2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole-1- on (222 mg) with compound X (317 mg) gave the free base of the title compound (100 mg). Maleate formation gave the title compound (85 mg), mp 164-166 ° C.

10 Analyse C22H25FN4° · C4H4°4Analysis C22H25FN4 ° C4H4 ° 4

Fundet: C, 62,5; H, 5,9; N, 11,0;Found: C, 62.5; H, 5.9; N, 11.0;

Beregnet: C, 62,9; H, 5,9; N, 11,3%.Calculated: C, 62.9; H, 5.9; N, 11.3%.

EKSEMPEL 14 6- Fluor-2,5-dihydro-5-methyl-2-[(5-methyl-lH-imidazol-4-15 yl)methyl]-lH-pyrido[4,3-b]indol-l-on-maleat 6-Fluor-2,5-dihydro-5-methyl-IH-pyrido[4,3 -b]indol-1-on (140 mg) blev blandet med forbindelse X (290 g) ifølge metoden fra eksempel 1, hvilket gav den fri base af titelforbindelsen (143 mg). Dette materiale blev opløst i dichlormethan:ethanol 20 (1:1, 20 ml) og behandlet med en opløsning af maleinsyre (56 mg) i ethanol (2 ml). Opløsningsmidlet blev fjernet i vakuum, hvilket gav et fast stof, som blev omkrystalliseret fra ethylacetat/methanol, hvilket gav titelforbindelsen (75 mg), smeltepunkt 183-184°C.EXAMPLE 14 6- Fluoro-2,5-dihydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indole-1- on-maleate 6-Fluoro-2,5-dihydro-5-methyl-1H-pyrido [4,3-b] indol-1-one (140 mg) was mixed with compound X (290 g) according to the method of Example 1 to give the free base of the title compound (143 mg). This material was dissolved in dichloromethane: ethanol 20 (1: 1, 20 ml) and treated with a solution of maleic acid (56 mg) in ethanol (2 ml). The solvent was removed in vacuo to give a solid which was recrystallized from ethyl acetate / methanol to give the title compound (75 mg), mp 183-184 ° C.

25 Analyse C17Hi5FN40 . C4H404Analysis C17Hi5FN40. C4H404

Fundet: C, 59,2; H, 4,3; N, 12,9;Found: C, 59.2; H, 4.3; N, 12.9;

Beregnet: C, 59,2; H, 4,5; N, 13,1%.Calculated: C, 59.2; H, 4.5; N, 13.1%.

6-Fluor-2,3,4,5-tetrahydro-5-methyl-2-[(5-propyl-lH-imidazol- 4-yl)methyl]-IH-pyrido[4,3-b]indol-l-on-maleat EKSEMPEL 15 35 DK 169922 B16-Fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-propyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indole-1 EXAMPLE 15 DK 169922 B1

Natriumhydrid (73%'s dispersion i olie; 66 mg) blev sat til 5 en omrørt suspension af 6-fluor-2,3,4,5-tetrahydro-5-methyl-IH-pyrido[4,3-b] indol-l-on (289 mg) i tør DME (30 ml), og blandingen blev opvarmet ved 60°C under nitrogen i 6 timer.Sodium hydride (73% dispersion in oil; 66 mg) was added to a stirred suspension of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indole. -l-one (289 mg) in dry DME (30 ml) and the mixture was heated at 60 ° C under nitrogen for 6 hours.

4- (Chlormethyl) - N, N - dimethyl - 5 - propyl - IH - imidaz ol -1 - sul f ona -mid (467 mg) blev derefter tilsat som en suspension i DME (5 10 ml), og omrøring blev fortsat ved 60°C i 18 timer. 2N saltsyre (2 ml) blev derefter tilsat, og blandingen blev opvarmet under tilbagesvaling i 5 timer. Blandingen blev hældt i 8%'s natriumhydrogencarbonatopløsning (100 ml) og ekstraheret med dichlormethan:ethanol (10:1; 4 x 50 ml). De samlede, tørrede, 15 organiske ekstrakter blev inddampet under reduceret tryk, hvilket gav et fast stof, som blev oprenset ved FCC under eluering med system A (100:10:1), hvilket gav den fri base af titelforbindelsen (279 mg) . Den fri base blev opløst i absolut ethanol (10 ml) og behandlet med en opløsning af malein-20 syre (100 mg) i absolut ethanol (2 ml). Ether (ca. 5 ml) blev sat til opløsningen, der afkøledes til udfældning af titel-forbindelsen (265 mg), smeltepunkt 145-148°C.4- (Chloromethyl) - N, N - dimethyl - 5 - propyl - 1H - imidazol - 1 - sulfonone (467 mg) was then added as a suspension in DME (5 ml) and stirring was continued. at 60 ° C for 18 hours. 2N hydrochloric acid (2 ml) was then added and the mixture was heated under reflux for 5 hours. The mixture was poured into 8% sodium bicarbonate solution (100 ml) and extracted with dichloromethane: ethanol (10: 1; 4 x 50 ml). The combined dried 15 organic extracts were evaporated under reduced pressure to give a solid which was purified by FCC eluting with System A (100: 10: 1) to give the free base of the title compound (279 mg). The free base was dissolved in absolute ethanol (10 mL) and treated with a solution of maleic acid (100 mg) in absolute ethanol (2 mL). Ether (about 5 ml) was added to the solution which was cooled to precipitate the title compound (265 mg), mp 145-148 ° C.

Analyse Ci9h21fn4o.c4h4o4Analysis Ci9h21fn4o.c4h4o4

Fundet: C, 60,6; H, 5,5; N, 12,1; 25 Beregnet: C, 60,5; H, 5,5; N, 12,3%.Found: C, 60.6; H, 5.5; N, 12.1; Calcd: C, 60.5; H, 5.5; N, 12.3%.

EKSEMPEL 17 6-Fluor-2,3,4,5-tetrahydro-2-[(5-methyl-lH-imidazol-4-yl)-methyl]-5-(2-propynyl)-IH-pyrido[4,3-b] indol-l-on-maleatExample 17 6-Fluoro-2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -5- (2-propynyl) -1H-pyrido [4, 3-b] indole-1-one maleate

En omrørt opløsning af 6-fluor-2,3,4,5-tetrahydro-2-[(5-30 methyl-l- (triphenylmethyl) -lH-imidazol-4-yl)methyl] -lH-pyri-do [4,3-b] indol-l-on (228 mg) i tør acetone (40 ml) og vandfri 36 DK 169922 B1 kaliumcarbonat (116 mg) blev behandlet med propargylbromid (10% v/v opløsning i tør acetone; 1 ml) og opvarmet ved tilbagesvaling natten over. Efter afkøling blev den overskydende acetone fjernet i vakuum, og remanensen blev fordelt mellem 5 vand (100 ml) og ethylacetat (100 ml). Den organiske fase blev vasket med vand (2 x 50 ml), og de samlede, vandige ekstrakter blev vasket med ethylacetat (50 ml). De samlede, organiske ekstrakter blev derefter koncentreret i vakuum, og remanensen blev opløst i en blanding af vand (10 ml), iseddi-10 kesyre (10 ml) og THF (15 ml) og opvarmet ved tilbagesvaling i 2 timer. Den afkølede opløsning blev derefter gjort basisk med 2N natriumhydroxid (ca. 100 ml) og ekstraheret med ethylacetat (2 x 100 ml). De samlede, tørrede, organiske ekstrakter blev adsorberet på silica og oprenset ved FCC under elue-15 ring med system A (100:8:1), hvilket gav den fri base af titelforbindelsen (95 mg). Denne blev opløst i den mindst mulige mængde varm, tør methanol, og maleinsyre (32 mg) blev tilsat. Opløsningen blev opvarmet og derefter hensat til afkøling. Ether blev tilsat til udfældning af titelforbindelsen 20 (80 mg), smeltepunkt 123-124°C.A stirred solution of 6-fluoro-2,3,4,5-tetrahydro-2 - [(5-30 methyl-1- (triphenylmethyl) -1H-imidazol-4-yl) methyl] -1H-pyrido [ 4,3-b] indol-1-one (228 mg) in dry acetone (40 ml) and anhydrous potassium carbonate (116 mg) were treated with propargyl bromide (10% w / v solution in dry acetone; 1 ml ) and heated at reflux overnight. After cooling, the excess acetone was removed in vacuo and the residue was partitioned between 5 water (100 ml) and ethyl acetate (100 ml). The organic phase was washed with water (2 x 50 ml) and the combined aqueous extracts were washed with ethyl acetate (50 ml). The combined organic extracts were then concentrated in vacuo and the residue dissolved in a mixture of water (10 ml), glacial acetic acid (10 ml) and THF (15 ml) and heated at reflux for 2 hours. The cooled solution was then basified with 2N sodium hydroxide (about 100 ml) and extracted with ethyl acetate (2 x 100 ml). The combined dried organic extracts were adsorbed on silica and purified by FCC eluting with system A (100: 8: 1) to give the free base of the title compound (95 mg). This was dissolved in the least amount of hot, dry methanol and maleic acid (32 mg) was added. The solution was heated and then allowed to cool. Ether was added to precipitate the title compound 20 (80 mg), mp 123-124 ° C.

Analyse c19h17fn4o.c4h4o4Analysis c19h17fn4o.c4h4o4

Fundet: C, 60,9; H, 4,7; N, 12,0;Found: C, 60.9; H, 4.7; N, 12.0;

Beregnet: C, 61,1; H, 4,7; N, 12,4%.Calculated: C, 61.1; H, 4.7; N, 12.4%.

EKSEMPEL 21 25 2,3,4,5-Tetrahydro-6-hydroxy-5-methyl-2-((5-methyl-lH-imida-zol-4-yl)methyl]-IH-pyrido[4,3-b]indol-l-on-maleatEXAMPLE 21 2,3,4,5-Tetrahydro-6-hydroxy-5-methyl-2 - ((5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3- b] indol-l-one maleate

En opløsning af 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-lH-imidazol-4-yl)methyl] -6- (phenylmethoxy) -lH-pyrido[4,3-b] in-dol-l-on (500 mg) i absolut ethanol (100 ml) blev hydrogen-30 eret ved stuetemperatur og atmosfærisk tryk over 10% palladium-på-trækul (50% vandig pasta; 100 mg) som katalysator i 6 timer. Blandingen blev derefter filtreret, koncentreret i * vakuum, og det resulterende faste stof blev omkrystalliseret 37 DK 169922 B1 fra ethanol (ca. 50 ml), hvilket gav den fri base af titelforbindelsen (90 mg). En del af den fri base i methanol blev behandlet med maleinsyre (18 mg), derefter opvarmet på dampbad i 10 minutter. Den resulterende opløsning blev koncen-5 treret i vakuum, og remanensen blev tritureret med ether (10 ml), hvilket gav titelforbindelsen (60 mg), smeltepunkt 200°C.A solution of 2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -6- (phenylmethoxy) -1H-pyrido [4,3- b] indole-1-one (500 mg) in absolute ethanol (100 ml) was hydrogenated at room temperature and atmospheric pressure over 10% palladium-on-charcoal (50% aqueous paste; 100 mg) as catalyst in 6 hours. The mixture was then filtered, concentrated in vacuo and the resulting solid was recrystallized from ethanol (about 50 ml) to give the free base of the title compound (90 mg). Part of the free base in methanol was treated with maleic acid (18 mg), then heated on a steam bath for 10 minutes. The resulting solution was concentrated in vacuo and the residue triturated with ether (10 mL) to give the title compound (60 mg), m.p. 200 ° C.

1H-NMR 52,37 (3H,s), 3,06 (2H,t), 3,65 (2H,t), 3,97 (3H,s), 4,65 (2H,s), 6,08 (2H,s), 6,58 (lH,d), 6,92 (lH,t), 7,45 10 (lH,d), 8,89 (IH,s).1 H NMR 52.37 (3H, s), 3.06 (2H, t), 3.65 (2H, t), 3.97 (3H, s), 4.65 (2H, s), δ 08 (2H, s), 6.58 (1H, d), 6.92 (1H, t), 7.45 (1H, d), 8.89 (1H, s).

EKSEMPEL 22 6-Fluor-2,3,4,5-tetrahydro-2-[(5-methyl-lH-imidazol-4-yl)-methyl]-lH-pyrido[4,3-b]indol-l-on-maleatEXAMPLE 22 6-Fluoro-2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indole-1- one maleate

En opløsning af 6-fluor-2,3,4,5-tetrahydro-2-[(5-methyl-lH-15 imidazol-4-yl)methyl]-5-(phenylmethoxymethyl)-lH-pyrido[4,3-b]indol-l-on (175 mg) i absolut ethanol (10 ml) og eddikesyre (2,5 ml) blev hydrogeneret ved stuetemperatur og atmosfærisk tryk over 10% palladium-på-trækul (50% vandig pasta; 45 mg) som katalysator i absolut ethanol (2 ml) i 20 timer. Mere 20 katalysator (45 mg) blev tilsat, og omrøring blev fortsat i 20 timer. Blandingen blev filtreret, og filtratet blev inddampet til tørhed. Remanensen blev behandlet med 8% natrium-hydrogencarbonatopløsning (50 ml) og ekstraheret med dichlor-methan (3 x 25 ml). De samlede, tørrede, organiske ekstrakter 25 blev inddampet, hvilket gav en olie (ca. 130 mg), som blev oprenset ved FCC under eluering med system A (150:10:1), hvilket gav den fri base af titelforbindelsen (102 mg). Denne blev opløst i ethanol (ca. 2 ml) og behandlet med en opløsning af maleinsyre (42 mg) i ethanol (0,5 ml). Opløsningsmid-30 let blev fjernet i vakuum, og remanensen blev tritureret med tør ether (5 x 5 ml), hvilket gav titelforbindelsen (120 mg), smeltepunkt 186-188°C.A solution of 6-fluoro-2,3,4,5-tetrahydro-2 - [(5-methyl-1H-15-imidazol-4-yl) methyl] -5- (phenylmethoxymethyl) -1H-pyrido [4.3 -b] indol-1-one (175 mg) in absolute ethanol (10 ml) and acetic acid (2.5 ml) was hydrogenated at room temperature and atmospheric pressure over 10% palladium-on-charcoal (50% aqueous paste; 45 mg ) as a catalyst in absolute ethanol (2 ml) for 20 hours. More 20 catalyst (45 mg) was added and stirring was continued for 20 hours. The mixture was filtered and the filtrate was evaporated to dryness. The residue was treated with 8% sodium hydrogen carbonate solution (50 ml) and extracted with dichloromethane (3 x 25 ml). The combined dried organic extracts were evaporated to give an oil (about 130 mg) which was purified by FCC eluting with System A (150: 10: 1) to give the free base of the title compound (102 mg ). This was dissolved in ethanol (about 2 ml) and treated with a solution of maleic acid (42 mg) in ethanol (0.5 ml). The solvent was removed in vacuo and the residue was triturated with dry ether (5 x 5 ml) to give the title compound (120 mg), mp 186-188 ° C.

38 DK 169922 B138 DK 169922 B1

Analyse Ci6H15FN40.C4H404Analysis C16H15FN40.C4H404

Fundet: C, 57,8; H, 4,7; N, 13,2;Found: C, 57.8; H, 4.7; N, 13.2;

Beregnet: C, 58,0; H, 4,6; N, 13,5%.Calculated: C, 58.0; H, 4.6; N, 13.5%.

EKSEMPEL 23 5 2,3,4,5-Tetrahydro-6-hydroxy-2-[(5-methyl-lH-imidazol-4- yl)methyl]-IH-pyrido[4,3-b]indol-l-on-maleatEXAMPLE 23 2,3,4,5-Tetrahydro-6-hydroxy-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indole-1- one maleate

En opløsning af 2,3,4,5-tetrahydro-2-[(5-methyl-lH-imidazol- 4-yl)methyl]-6-(phenylmethoxy)-5-[(phenylmethoxy)methyl]-1H-pyrido[4,3-b]indol-l-on (600 mg) i absolut ethanol (80 ml) og 10 iseddikesyre (4 ml) blev hydrogeneret ved stuetemperatur og atmosfærisk tryk over 10% palladium-på-trækul (50% vandig pasta; 100 mg) som katalysator i 24 timer. Blandingen blev derefter filtreret, og filtratet blev koncentreret i vakuum. Remanensen blev behandlet med 8% natriumhydrogencarbonatop-15 løsning (ca. 150 ml) og filtreret. Det filtrerede, faste stof blev derefter vasket med vand (ca. 100 ml), opløst i ethanol (200 ml) og koncentreret i vakuum, hvilket gav et fast stof (320 mg), som blev oprenset ved FCC under eluering med system A (100:8:1), hvilket gav den fri base af titelforbindelsen 20 (100 mg). En opløsning af den fri base (100 mg) i methanol (20 ml) blev behandlet med maleinsyre (39 mg). Opløsningen blev opvarmet på et dampbad i 10 minutter og koncentreret i vakuum. En opløsning af remanensen i methanol (2 ml) blev behandlet med ether (ca. 80 ml), hvilket gav titelforbindel-25 sen (100 mg), smeltepunkt 130CC.A solution of 2,3,4,5-tetrahydro-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -6- (phenylmethoxy) -5 - [(phenylmethoxy) methyl] -1H-pyrido [4,3-b] indol-1-one (600 mg) in absolute ethanol (80 ml) and 10 glacial acetic acid (4 ml) were hydrogenated at room temperature and atmospheric pressure over 10% palladium-on-charcoal (50% aqueous paste) ; 100 mg) as a catalyst for 24 hours. The mixture was then filtered and the filtrate was concentrated in vacuo. The residue was treated with 8% sodium bicarbonate solution (about 150 ml) and filtered. The filtered solid was then washed with water (about 100 ml), dissolved in ethanol (200 ml) and concentrated in vacuo to give a solid (320 mg) which was purified by FCC eluting with system A ( 100: 8: 1) to give the free base of the title compound 20 (100 mg). A solution of the free base (100 mg) in methanol (20 ml) was treated with maleic acid (39 mg). The solution was heated on a steam bath for 10 minutes and concentrated in vacuo. A solution of the residue in methanol (2 ml) was treated with ether (about 80 ml) to give the title compound (100 mg), m.p.

TLC (system A, 100:8:1) (2 x eluering), Rf 0,3.TLC (system A, 100: 8: 1) (2x elution), Rf 0.3.

* i EKSEMPEL· 24 6-Fluor-2,3,4,5-tetrahydro-5-methyl-2 -[(5-methyl-IH-imidazol- 4-yl)methyl]-ΙΗ-pyrido[4,3-b]indol-1-on-hydrochlorid 39 DK 169922 B1* In EXAMPLE 24 6-Fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -pyrido [4,3- b] indole-1-one hydrochloride

En opløsning af 6-fluor-2,3,4,5-tetrahydro-5-methyl-2-[ (5-5 methyl-IH-imidazol-4-yl) methyl] -lH-pyrido [4,3-b] indol-l-on (260 mg) i methanol (10 ml) blev behandlet med etherisk hydrogenchlorid, og blandingen blev derefter koncentreret i vakuum. Remanensen blev tritureret med ether (15 ml), hvilket gav titelforbindelsen (230 mg) som et fast stof, smeltepunkt 10 275-278°C.A solution of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2- [(5-5 methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b ] indol-1-one (260 mg) in methanol (10 ml) was treated with ethereal hydrogen chloride and the mixture was then concentrated in vacuo. The residue was triturated with ether (15 mL) to give the title compound (230 mg) as a solid, mp 10 275-278 ° C.

Vandanalyse fundet 3,73 vægtprocent s 0,75 mol H20.Water analysis found 3.73 wt.% 0.75 mol H2 O.

Analyse C17H17FN4O.HC1.0,75 H20Analysis C17H17FN4O.HC1.0.75 H2 O

Fundet: C, 55,8; H, 5,3; N, 15,2;Found: C, 55.8; H, 5.3; N, 15.2;

Beregnet: C, 56,3; H, 5,4; N, 15,4%.Calculated: C, 56.3; H, 5.4; N, 15.4%.

15 EKSEMPEL 25 6 - Fluor-2,3,4,5- tetrahydro- 5 -methyl -2 - [ (5 -methyl - IH- imidazol - 4-yl)methyl]-ΙΗ-pyrido[4,3-b]indol-l-on-benzoatEXAMPLE 25 6 - Fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -ΙΗ-pyrido [4,3-b] indole-l-one benzoate

En opløsning af 6-fluor-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl - IH- imidazol - 4 - yl) methyl ] - ΙΗ-pyrido [4,3-b] indol -1 - on 20 (170 mg) i methanol (10 ml) blev behandlet med benzoesyre (66 mg). Ether (ca. 20 ml) blev tilsat til udfældning af et fast stof, som blev filtreret fra, hvilket gav titelforbindelsen (220 mg), smeltepunkt 169-171°C.A solution of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -ΙΗ-pyrido [4,3-b] indole -1-on 20 (170 mg) in methanol (10 ml) was treated with benzoic acid (66 mg). Ether (about 20 ml) was added to precipitate a solid which was filtered off to give the title compound (220 mg), mp 169-171 ° C.

Analyse Cl7H17^40 · ^7¾¾ 25 Fundet: C, 66,3; H, 5,4; N, 12,8;Analysis C17H17440.77 Found: C, 66.3; H, 5.4; N, 12.8;

Beregnet: C, 66,3; H, 5,3; N, 12,9%.Calculated: C, 66.3; H, 5.3; N, 12.9%.

EKSEMPEL 26 6-Fluor-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-lH-imidazol- 4-yl)methyl]-lH-pyrido[4,3-b]indol-l-on 40 DK 169922 B1 *Example 26 6-Fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3-b] indole -l-on 40 DK 169922 B1 *

En opløsning af 6-fluor-2,3,4,5-tetrahydro-5-methyl-lH-pyri-5 do[4,3-b]-indol-l-on (100 mg) i N-methylpyrrolidinon (10 ml) blev behandlet med 4-toluensulfonsyremonohydrat (17 mg) og 4-hydroxymethyl-5-methylimidazolhydrochlorid (37 mg). Blandingen blev derefter opvarmet til 125°C i 18 timer, i hvilket tidsrum tre yderligere portioner 4-hydroxymethyl -5-methylimi-10 dazolhydrochlorid (37 mg) blev tilsat efter henholdsvis 1,2 og 3 timer. Opløsningen blev derefter hældt i 8% natrium-hydrogencarbonatopløsning (100 ml) og ekstraheret med di-chlormethan (3 x 100 ml). De samlede ekstrakter blev koncentreret i vakuum, og N-methylpyrrolidinon blev destilleret 15 ved 100°C. Remanensen blev oprenset ved FCC under eluering med system A (200:8:1), hvilket gav titelforbindelsen (100 mg), TLC (system A 100:8:1), Rf 0,3.A solution of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-1H-pyrido [4,3-b] indol-1-one (100 mg) in N-methylpyrrolidinone (10 ml) was treated with 4-toluenesulfonic acid monohydrate (17 mg) and 4-hydroxymethyl-5-methylimidazole hydrochloride (37 mg). The mixture was then heated to 125 ° C for 18 hours, during which three additional portions of 4-hydroxymethyl-5-methylimidazole hydrochloride (37 mg) were added after 1.2 and 3 hours, respectively. The solution was then poured into 8% sodium hydrogen carbonate solution (100 ml) and extracted with dichloromethane (3 x 100 ml). The combined extracts were concentrated in vacuo and N-methylpyrrolidinone was distilled at 100 ° C. The residue was purified by FCC eluting with system A (200: 8: 1) to give the title compound (100 mg), TLC (system A 100: 8: 1), Rf 0.3.

^-NMR 52,36 (3H,s), 3,12 (2H,t), 3,6 (2H,t), 3,90 (3H,s), 4,66 (2H,s), 6,07 (2H,s), 6,95-7,2 (2H,m), 7,80 (lH,d), 8,80 20 (IH,S).1 H-NMR 52.36 (3H, s), 3.12 (2H, t), 3.6 (2H, t), 3.90 (3H, s), 4.66 (2H, s), 6, 07 (2H, s), 6.95-7.2 (2H, m), 7.80 (1H, d), 8.80 (1H, S).

Følgende eksempler illustrerer farmaceutiske præparater ifølge opfindelsen indeholdende 6-fluor-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-IH-imidazol-l-yl)methyl]-lH-pyrido[4,3-b]indol-l-on som aktiv bestanddel. Fysiologisk acceptable 25 salte og/eller solvater af denne forbindelse og andre forbindelser med formlen (I) og fysiologisk acceptable salte og/eller solvater deraf kan formuleres på tilsvarende vis.The following examples illustrate pharmaceutical compositions of the invention containing 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-1-yl) methyl] -1H-pyrido [4 , 3-b] indol-1-one as active ingredient. Physiologically acceptable salts and / or solvates of this compound and other compounds of formula (I) and physiologically acceptable salts and / or solvates thereof may be similarly formulated.

Tabletter til oral administrationTablets for oral administration

Tabletter kan fremstilles ved sædvanlige metoder såsom direk-30 te komprimering eller vådgranulering.Tablets may be prepared by conventional methods such as direct compression or wet granulation.

KK

i 41 DK 169922 B1in 41 DK 169922 B1

Tabletterne kan overtrækkes med egnede filmdannende materialer, såsom hydroxypropylmethylcellulose, under anvendelse af standardteknikker. Alternativt kan tabletterne være sukker-overtrukne.The tablets can be coated with suitable film-forming materials, such as hydroxypropylmethyl cellulose, using standard techniques. Alternatively, the tablets may be sugar-coated.

5 Direkte komprimering5 Direct compression

Tablet mg/tabletTablet mg / tablet

Aktiv bestanddel 1,00Active ingredient 1.00

Vandfrit lactose USNF 79,00Anhydrous lactose USNF 79.00

Mikrokrystallinsk cellulose USNF 19,55 10 Magnesiumstearat BP 0,45Microcrystalline cellulose USNF 19.55 Magnesium stearate BP 0.45

Komprimeringsvægt 90,00 * Af en kvalitet, der er egnet til direkte komprimeringCompression weight 90.00 * Of a quality suitable for direct compression

Den aktive bestanddel sigtes gennem en sigte med 0,25 mm 15 maskeåbning (60 mesh), blandes med vandfrit lactose, mikrokrystallinsk cellulose og magnesiumstearat. Den resulterende blanding komprimeres til tabletter, idet der anvendes en egnet tabletmaskine udstyret med stempler, der har en diameter på 5,5 mm.The active ingredient is screened through a 0.25 mm mesh (60 mesh) screen, mixed with anhydrous lactose, microcrystalline cellulose and magnesium stearate. The resulting mixture is compressed into tablets using a suitable tablet machine equipped with pistons having a diameter of 5.5 mm.

20 Tabletter med andre styrker kan fremstilles ved ændring af forholdet mellem den aktive bestanddel og lactose eller ændring af komprimeringsvægten og under anvendelse af passende stempler.Tablets of other strengths can be prepared by changing the ratio of the active ingredient to lactose or by changing the compressive weight and using appropriate pistons.

Sublingual tablet mg/tablet 25 Aktiv bestanddel 1,00Sublingual tablet mg / tablet Active ingredient 1.00

Komprimerbart sukker NF 64,00Compressible sugar NF 64.00

Magnesiumstearat BP 0,5Magnesium stearate BP 0.5

Komprimeringsvægt 65,00 42 DK 169922 B1Compression weight 65.00 42 DK 169922 B1

Den aktive bestanddel sigtes gennem en egnet sigte, blandes med hjælpestofferne og komprimeres under anvendelse af egnede stempler.The active ingredient is sieved through a suitable sieve, mixed with the excipients and compressed using suitable pistons.

Tabletter med andre styrker kan fremstilles ved ændring af 5 enten forholdet mellem aktiv bestanddel og hjælpestoffer eller komprimeringsvægten og under anvendelse af egnede stempler.Tablets of other strengths can be prepared by changing either the ratio of active ingredient to excipients or the compressive weight and using suitable pistons.

VådgranuleringWet granulation

Konventionel tablet mg/tablet 10 Aktiv bestanddel 1,0Conventional tablet mg / tablet Active ingredient 1.0

Lactose BP 153,0Lactose BP 153.0

Stivelse BP 30,0Starch BP 30.0

Prægelatineret majsstivelse BP 15,0Pre-laminated corn starch BP 15.0

Magnesiumstearat BP 1,5 15 _Magnesium stearate BP 1.5 15

Komprimeringsvægt 200,00Compression weight 200.00

Den aktive bestanddel sigtes gennem en egnet sigte og blandes med lactose, stivelse og prægelatineret majsstivelse. Passende volumener af renset vand tilsættes, og pulveret granu-20 leres. Efter tørring sigtes granulatet og blandes med magnesiums tearat. Granulatet komprimeres derefter til tabletter under anvendelse af stempler, der har en diameter på 7 mm.The active ingredient is sieved through a suitable sieve and mixed with lactose, starch and pregelatinized corn starch. Appropriate volumes of purified water are added and the powder granulated. After drying, the granulate is sieved and mixed with magnesium tearate. The granules are then compressed into tablets using pistons having a diameter of 7 mm.

Tabletter med andre styrker kan fremstilles ved ændring af forholdet mellem den aktive bestanddel og lactose eller 25 ændring af komprimeringsvægten og under anvendelse af egnede stempler.Tablets of other strengths can be prepared by changing the ratio of the active ingredient to lactose or by changing the compressive weight and using suitable pistons.

e i 43 DK 169922 B1e i 43 DK 169922 B1

Sublingual tablet mg/tabletSublingual tablet mg / tablet

Aktiv bestanddel 1,0Active ingredient 1.0

Mannitol BP 58,0Mannitol BP 58.0

Hydroxypropylmethylcellulose 5,0 5 Magnesiumstearat BP 1,0Hydroxypropyl methylcellulose 5.0 Magnesium stearate BP 1.0

Komprimeringsvægt 65,00Compression weight 65.00

Den aktive bestanddel sigtes gennem en egnet sigte og blandes med mannitol og hydroxypropylmethylcellulose. Passende volum-10 ener renset vand tilsættes, og pulveret granuleres. Efter tørring sigtes granulatet og blandes med magnesiumstearat. Granulatet komprimeres til tabletter under anvendelse af egnede stempler.The active ingredient is sieved through a suitable sieve and mixed with mannitol and hydroxypropyl methyl cellulose. Appropriate volume of purified water is added and the powder granulated. After drying, the granulate is sieved and mixed with magnesium stearate. The granulate is compressed into tablets using suitable pistons.

Tabletter med andre styrker kan fremstilles ved ændring af 15 forholdet mellem den aktive bestanddel og mannitol eller ændring af komprimeringsvægten og under anvendelse af egnede stempler.Tablets of other strengths can be prepared by changing the ratio of the active ingredient to mannitol or changing the compressive weight and using suitable pistons.

Kapsler mg/kapselCapsules mg / capsule

Aktiv bestanddel 1,0 20 * Stivelse 1500 98,0Active ingredient 1.0 20 * Starch 1500 98.0

Magnesiumstearat BP 1,0 Påfyldningsvægt 100,00 * En kvalitet, der er egnet til direkte komprimering 25 Den aktive bestanddel sigtes og blandes med hjælpestofferne. Blandingen fyldes på hårde gelatinekapsler størrelse nr. 2 under anvendelse af en egnet maskine. Andre doser kan fremstilles ved at ændre påfyldningsvægten og om nødvendigt ved at ændre kapselstørrelsen tilsvarende.Magnesium stearate BP 1.0 Filling weight 100.00 * A quality suitable for direct compression 25 The active ingredient is sieved and mixed with the excipients. The mixture is filled into size 2 hard gelatin capsules using a suitable machine. Other doses can be prepared by changing the filling weight and, if necessary, by changing the capsule size accordingly.

44 DK 169922 B1 I de ovenfor nævnte eksempler med tabletter og kapsler justeres mængden af hovedhjælpestoffet tilsvarende, når den aktive bestanddel er indeholdt som et egnet salt.In the above examples of tablets and capsules, the amount of the main excipient is adjusted accordingly when the active ingredient is contained as a suitable salt.

Syrup 5 Dette kan være enten et sucroseholdigt eller et sucrosefrit præparat.Syrup 5 This can be either a sucrose-containing or a sucrose-free preparation.

A. Sucroseholdig syrup πισ/5 ml dosisA. Sucrose-containing syrup πισ / 5 ml dose

Aktiv bestanddel 1,0Active ingredient 1.0

Sucrose BP 2750,0 10 Glycerin BP 500,0Sucrose BP 2750.0 10 Glycerin BP 500.0

Buffer )Buffer)

Aromastof )Flavor)

Farvestof ) efter behovDye) as needed

Konserveringsmiddel ) 15 Renset vand BP til 5,0 mlPreservative) Purified water BP to 5.0 ml

Den aktive bestanddel, buffer, aromastof, farvestof og konserveringsmiddel opløses i noget af vandet, og glycerin tilsættes. Den resterende mængde vand opvarmes til opløsning af sucrosen og afkøles derefter. De to opløsninger kombi-20 neres, justeres til volumen og blandes. Syruppen klares ved filtrering.The active ingredient, buffer, flavor, dye and preservative are dissolved in some of the water and glycerine is added. The remaining amount of water is heated to dissolve the sucrose and then cooled. The two solutions are combined, adjusted to volume and mixed. The syrup is cleared by filtration.

B. Sucrosefri syrup mg/5 ml dosisB. Sucrose-free syrup mg / 5 ml dose

Aktiv bestanddel 1,0Active ingredient 1.0

Hydroxypropylmethylcellulose USPHydroxypropylmethylcellulose USP

25 (viskositetstype 4000) 22,5(Viscosity type 4000) 22.5

Buffer )Buffer)

Aromastof )Flavor)

Farvestof ) efter behovDye) as needed

Konserveringsmiddel ) 30 Sødemiddel )Preservative) 30 Sweetener)

Renset vand BP til 5,0 ml vPurified water BP to 5.0 ml v

CC

45 DK 169922 B145 DK 169922 B1

Hydroxypropylmethylcellulosen dispergeres i varmt vand, afkøles og blandes derefter med en vandig opløsning indeholdende den aktive bestanddel og de andre formuleringskomponenter. Den resulterende opløsning justeres til volumen og blandes.The hydroxypropylmethyl cellulose is dispersed in hot water, cooled and then mixed with an aqueous solution containing the active ingredient and the other formulation components. The resulting solution is adjusted to volume and mixed.

5 Syruppen klares ved filtrering.The acid group is cleared by filtration.

Injektionspræparat til intravenøs administration mg/mlInjection preparation for intravenous administration mg / ml

Aktiv bestanddel 0,05 0,5Active ingredient 0.05 0.5

Natriumchlorid BP efter behov efter behov 10 Vand til injektion BP til 1,0 ml 1,0 mlSodium chloride BP as needed as needed 10 Water for injection BP to 1.0 ml 1.0 ml

Natriumchlorid kan tilsættes til justering af opløsningens tonicitet, og pH kan under anvendelse af syre eller base justeres til den pH-værdi med optimal stabilitet og/eller for at fremme opløsning af den aktive bestanddel. Alternativt kan 15 der anvendes egnede buffersalte.Sodium chloride can be added to adjust the tonicity of the solution, and the pH can be adjusted to the pH value with optimum stability and / or to promote dissolution of the active ingredient using acid or base. Alternatively, suitable buffer salts may be used.

Opløsningen fremstilles, klares og påfyldes ampuller af passende størrelse, der lukkes ved smeltning af glasset. Injektionsvæsken steriliseres ved opvarmning i en autoklave under anvendelse af én af de acceptable cykler. Alternativt 20 kan opløsningen steriliseres ved filtrering og påfyldes sterile ampuller under aseptiske betingelser. Opløsningen kan emballeres under en inert atmosfære af nitrogen eller anden egnet gas.The solution is prepared, clarified and filled with ampoules of appropriate size, which are sealed by melting the glass. The injection fluid is sterilized by heating in an autoclave using one of the acceptable cycles. Alternatively, the solution can be sterilized by filtration and charged to sterile ampoules under aseptic conditions. The solution may be packaged under an inert atmosphere of nitrogen or other suitable gas.

Trykaerosol med afmålt dosis 25 Suspensionsaerosol ma/afmålt dosis pr. beholderPressure aerosol with metered dose 25 Suspension aerosol ma / metered dose per container

Aktiv bestanddel, mikroniseret 0,050 12,0 mgActive ingredient, micronized 0.050 12.0 mg

Lecithin USNF 0,020 4,80 mgLecithin USNF 0.020 4.80 mg

Trichlorfluormethan BP 23,64 5,67 g 30 Dichlordifluormehtan BP 61,25 14,70 gTrichlorofluoromethane BP 23.64 5.67 g Dichlorodifluoromethane BP 61.25 14.70 g

Den aktive bestanddel mikroniseres i en fluid energy-mølle til et fint partikelstørrelsesområde. Lecithinen blandes med DK 169922 B1 46 .The active ingredient is micronized in a fluid energy mill to a fine particle size range. The lecithin is mixed with DK 169922 B1 46.

trichlorfluormethan ved en temperatur på 10-15°C, og det mikroniserede lægemiddelstof iblandes opløsningen med en høj - * forskydningsblander. Suspensionen afmåles i aluminiumaerosol-beholdere, og egnede måleventiler beregnet til afgivelse af 5 85 mg suspension påsættes beholderen, og dichlorfluormethan påfyldes beholderne under tryk gennem ventilerne.trichlorofluoromethane at a temperature of 10-15 ° C, and the micronized drug substance is admixed with a high shear mixer. The suspension is metered into aluminum aerosol containers, and suitable metering valves intended to deliver 5 85 mg of suspension are loaded onto the container and dichlorofluoromethane is filled into the containers under pressure through the valves.

Opløsningsaerosol mq/afmålt dosis pr. beholderSolution aerosol mq / metered dose per container

Aktiv bestanddel, mikroniseret 0,05 12,0 mg 10 Ethanol BP 7,500 1,80 mgActive ingredient, micronized 0.05 12.0 mg 10 Ethanol BP 7.500 1.80 mg

Trichlorfluormethan BP 18,875 4,53 gTrichlorofluoromethane BP 18.875 4.53 g

Dichlordifluormehtan BP 48,525 11,65 gDichlorodifluoromethane BP 48.525 11.65 g

Oliensyre BP, eller et egnet overfladeaktivt middel, fx Span 85 (sorbitantrioleat) kan også medtages.Oleic acid BP, or a suitable surfactant, eg Span 85 (sorbitan trioleate) may also be included.

15 Den aktive bestanddel opløses i ethanol sammen med oleinsyren eller overfladeaktivt middel, hvis det anvendes. Den alkoholiske opløsning afmåles i egnede aerosolbeholdere efterfulgt af trichlorfluormethan. Egnede måleventiler påsættes beholderne og dichlorfluormethan påfyldes dem under tryk gennem 20 ventilerne.The active ingredient is dissolved in ethanol together with the oleic acid or surfactant, if used. The alcoholic solution is measured in suitable aerosol containers followed by trichlorofluoromethane. Suitable metering valves are applied to the containers and dichlorofluoromethane is charged to them through the valves.

Inhalationspatroner mg/patronInhalation cartridges mg / cartridge

Aktiv bestanddel (mikroniseret) 0,05Active ingredient (micronized) 0.05

Lactose BP til 25,00 25 Den aktive bestanddel mikroniseres i en fluid energy-mølle til et fint partikelstørrelsesområde forud for blanding med lactose med en størrelsesorden som ved sædvanlig tabletfremstilling i et high energy-blandeudstyr. Pulverblandingen påfyldes hårde gelatinekapsler nr. 3 med en egnet maskine.Lactose BP to 25.00 25 The active ingredient is micronized in a fluid energy mill to a fine particle size range prior to mixing with lactose of the order of usual tablet preparation in a high energy mixing equipment. The powder mixture is filled with hard gelatin capsules # 3 with a suitable machine.

30 Indholdet af patronerne administreres under anvendelse af en pulverinhalator.The contents of the cartridges are administered using a powder inhaler.

Claims (7)

47 DK 169922 B1 Suppositorier Aktiv bestanddel 1,0 mg * Witepsol H15 til 1,0 g * Witepsol H15 er navnebeskyttet kvalitet af Adeps Solidus 5 Ph. Eur. En suspension af den aktive bestanddel fremstilles i den smeltede Witepsol og fyldes under anvendelse af en egnet maskine i 1 g suppositorieforme.47 DK 169922 B1 Suppositories Active ingredient 1.0 mg * Witepsol H15 to 1.0 g * Witepsol H15 is the proprietary quality of Adeps Solidus 5 Ph. Eur. A suspension of the active ingredient is prepared in the molten Witepsol and filled using a suitable machine in 1 g suppository molds. 1. Substituerede (imidazol-4-yl)methylpyrido-, og -azepino-, indolonderivater med den almene formel (I) O O' /"N^lrn VvLy Q 'R1 hvor Im betegner en imidazolylgruppe med formlen: W — Ή' N^NH ΗΝχ^Ν1. Substituted (imidazol-4-yl) methylpyrido, and -azepino, indolone derivatives of the general formula (I) OO '/ "N ^ lrn VvLy Q' R1 wherein Im represents an imidazolyl group of the formula: W - Ή 'N ^ NH ΗΝχ ^ Ν 15 R1 betegner hydrogen, C^-alkyl, C3.4-alkynyl eller C4_6-cycloalkylmethyl; R4 betegner C^-alkyl; Y betegner CH=CH eller (CH2)n, hvor n betegner tallet 2 eller 3; Q betegner halogen, hydroxy, phenyl-Clm3-alkoxy, -alkyl 20 eller cyano; Q' betegner hydrogen eller fluor; 48 DK 169922 B1 og fysiologisk acceptable salte og solvater deraf.R 1 represents hydrogen, C 1-4 alkyl, C 3-4 alkynyl or C 4-6 cycloalkylmethyl; R 4 represents C 1-4 alkyl; Y represents CH = CH or (CH 2) n, where n represents 2 or 3; Q represents halogen, hydroxy, phenyl-C1-3 alkoxy, alkyl or cyano; Q 'represents hydrogen or fluorine; 48 DK 169922 B1 and physiologically acceptable salts and solvates thereof. 2. Derivater ifølge krav 1, kendetegnet ved, at Y betegner gruppen (CH2)2, og Q betegner hydrogen. 5 3. 6-Fluor-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-lH-imida- zol-4-yl)methyl]-lH-pyrido [4,3-b] indol-l-on og fysiologisk acceptable salte og solvater deraf.Derivatives according to claim 1, characterized in that Y represents the group (CH 2) 2 and Q represents hydrogen. 3. 6-Fluoro-2,3,4,5-tetrahydro-5-methyl-2 - [(5-methyl-1H-imidazol-4-yl) methyl] -1H-pyrido [4,3- b] indole-1-one and physiologically acceptable salts and solvates thereof. 4. Fremgangsmåde til fremstilling af et derivat med den almene formel (I) ifølge et hvilket som helst af kravene 1-3 10 eller et fysiologisk acceptabelt salt eller solvat deraf, kendetegnet ved, at: (A) en forbindelse med formlen (II) O r TVY (ii> q R1 hvor Q, Q', R1 og Y har de i krav 1 anførte betydninger, 15 alkyleres med en forbindelse med formlen (III) X-Im (III) eller et beskyttet derivat deraf, hvor Im har de i krav 1 anførte betydninger og X betegner en gruppe -CH2L, og L betegner en fraspaltelig enhed, og omsætningen udføres i 20 nærværelse af en base? eller X betegner -CH2OH, og omsætningen udføres i nærværelse af en syre ved forhøjet temperatur efterfulgt om nødvendigt af fjernelse af eventuelle tilstedeværende beskyttelsesgrupper? eller (B) en forbindelse med den almene formel (I) omdannes til en 25 anden forbindelse med formlen (I) under anvendelse af konventionelle teknikker? eller < « 49 DK 169922 B1 (C) beskyttelsesgrupper fjernes fra en beskyttet form af en forbindelse med formlen (I), og, når forbindelsen med formlen (I) opnås som en blanding af enantiomerer, blandingen eventuelt opspaltes for at opnå den 5 ønskede enantiomer; og/eller, når forbindelsen med formlen (I) foreligger i form af fri base, den fri base eventuelt omdannes til et salt.Process for the preparation of a derivative of the general formula (I) according to any one of claims 1-3 or a physiologically acceptable salt or solvate thereof, characterized in that: (A) a compound of the formula (II) O is TVY (ii> q R1 wherein Q, Q ', R1 and Y have the meanings set forth in claim 1, alkylated with a compound of formula (III) X-Im (III) or a protected derivative thereof wherein Im has the meanings given in claim 1 and X represents a group -CH 2 L and L represents a leaving group and the reaction is carried out in the presence of a base? or X represents -CH 2 OH and the reaction is carried out in the presence of an acid at elevated temperature followed by or (B) converting a compound of general formula (I) into another compound of formula (I) using conventional techniques? or <«49 DK 169922 B1 (C) removing groups from a bes chopped form of a compound of formula (I) and, when the compound of formula (I) is obtained as a mixture of enantiomers, the mixture is optionally digested to obtain the desired enantiomer; and / or, when the compound of formula (I) is in the form of free base, the free base is optionally converted into a salt. 5. Farmaceutisk præparat, kendetegnet ved, at det omfatter mindst ét derivat 10 med den almene formel (I) ifølge krav 1 eller et fysiologisk acceptabelt salt eller solvat deraf sammen med mindst ét fysiologisk acceptabelt bærestof eller hjælpestof.Pharmaceutical composition, characterized in that it comprises at least one derivative 10 of the general formula (I) according to claim 1 or a physiologically acceptable salt or solvate thereof together with at least one physiologically acceptable carrier or excipient. 6. Farmaceutisk præparat ifølge krav 5, kendetegnet ved, at det foreligger i en form, der 15 er beregnet til oral eller parenteral administration.Pharmaceutical composition according to claim 5, characterized in that it is in a form which is intended for oral or parenteral administration.